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Is Parkinson death rate increasing?

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Here is a report that more than twice as many Americans dying from Parkinson disease in 2019 (35,311) compared with 1999 (14,593). The study was published in the November 16, 2021, issue of Neurology.

Using data obtained from the National Vital Statistics System of the National Center for Health Statistics, the researchers calculated a total of 479,059 U.S. deaths from Parkinson disease between 1999 and 2019.

The age-adjusted death rate nearly double in 20 years, from 1999 to 2019. There was an average annual increase of 2.4% over the two decades.

Parkinson disease mortality increased significantly in all age groups, sexes, and racial and ethnic groups, as well as in urban and rural locations. There were, however, several notable differences within these categories. Mortality rates for men were twice those for women throughout the study period. Also, White individuals had higher mortality rates than people from other racial or ethnic groups which implies there is some genetic aspect.

The scientists speculate that that increased exposure to pesticides, herbicides, heavy metals, and air pollution, could raise Parkinson disease risk. However a doubling death rate would mean a rather obvious change in environment The scientists speculate that as people are living longer, thereby contributing to higher Parkinson disease incidence and mortality. Yet in US the life expectancy didn't increase during that period.

Most patients die with Parkinson’s Disease and not from it. The illnesses that kill most people are the same as those that kill people with PD. These are heart conditions, stroke and cancer. As we age we become increasingly aware that more than one bad thing can happen to our bodies.

Is misfolded protein aggregation linked to ribosomes degradation with age?

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Definitely since the beginning of the year, we have seen important publications in the neurodegenerative field. This concerns a fundamental aspect of research, rather than a clinical aspect.

Many age-related diseases, including Alzheimer's and Parkinson's, are caused by the aggregation of misfolded proteins that seem to be parked in the cytosol, instead of being shipped to where they should operate. The mechanisms underlying how aging causes protein aggregation are largely unknown.

Since protein synthesis is energetically expensive, the ribosome must balance the costs of efficiently manufacturing a protein with those of correctly folding it. enter image description here When correctly folded, proteins perform their functions and remain soluble in the environment of the cell. However, larger proteins naturally have greater conformational variety, so the folding of these proteins requires tight control to ensure that the folding does not occur in one of multiple unproductive or misfolded pathways. cannot work properly and tend to stick to each other and other proteins, obstructing cellular processes and forming toxic aggregates.

Researchers at Stanford University have particularly studied the functioning of ribosomes and the influence of their dysfunction on the production of misfolded proteins.

In fact, the outer (cytosolic) face of the rough endoplasmic reticulum is dotted with ribosomes, but they are also found throughout the cytoplasm.

The role of the ribosome is to make new proteins. It does this by moving along a strand of messenger RNA and building a protein based on the code it reads. Making a protein this way is called translation. There are up to 10 million ribosomes in each cell.

Generating a functional proteome requires the ribosome to carefully regulate the disparate co-translational processes that determine the fate of nascent polypeptides. The non-uniform rate of translation elongation that defines translation kinetics appears to be the primary means of regulating this trade-off. enter image description here

In new research published Jan. 19 in Nature, these researchers attributed this problem to a deficiency in the ribosomal machinery, which deficiency is age-related. Researchers in the lab of Judith Frydman, Donald Kennedy Professor of the Stanford School of Humanities, used two well-established models of human aging, yeast and roundworms. Aging modifies the elongation kinetics of translation in Caenorhabditis elegans and Saccharomyces cerevisiae.

Ribosome pausing was exacerbated at specific positions in yeast and aged worms, including polybasic stretch, resulting in increased ribosome collisions known to trigger ribosome-associated quality control (RQC). Notably, aged yeast cells exhibited impaired clearance and increased aggregation of RQC substrates.

Very small changes in folding efficiency with age will intensify in a vicious circle where translational defects lead to system overload, which in turn leads to increased protein aggregates with age which are themselves also toxic.

Why L-dopa, the drug used for treating Parkinson's disease, loses efficacy and causes dyskinesia as treatment progresses.

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Paradoxically, the therapy that improves the quality of life of patients with Parkinson's disease is the one that later contributes to the decline in their quality of life. Indeed over time, L-dopa (l-3,4-Dihydroxyphenylalanine), the main treatment for Parkinson's disease, loses its effectiveness and causes involuntary muscle movements and erratic movements and sometimes hallucinations. Although this effect is well identified, scientists did not understand why L-dopa accelerates the progression of the disease.

L-dopa and other pharmacological treatments for Parkinson's disease are designed to replace lost dopamine caused by degenerating nerve cells in the brain. Although dopamine cannot cross the blood-brain barrier, which allows substances such as water and oxygen to pass into the brain, L-dopa can. However, 99% of L-dopa is metabolized outside the brain, so it is given in combination with an enzyme inhibitor to prevent side effects such as nausea and heart problems, and allow more of the drug remains in the blood so as to be percolated through the blood-brain barrier. In this case, 5 to 10% of the ingested dose reaches the brain.

A team of researchers from the University of California, Irvine studied the molecular binding characteristics of L-dopa and related compounds using an optical technology called surface plasmon resonance to measure interactions between the drug and the target proteins. The results of the study were recently published in ACS Chemical Neuroscience. enter image description here

Their studies aimed to test whether continuous administration of L-dopa in animal models of Parkinson's disease is associated with increased iron accumulation in dopaminergic neurons in the brain and whether this accumulation depends on the binding of L-dopa to siderocalin.

The researchers also wanted to determine whether the complex can be detected in the blood of patients with Parkinson's disease. The relative amount of this complex would then serve as a biomarker to determine when it becomes appropriate to switch to new treatments for the disease.

Indeed l-DOPA chelates iron through its catechol group, is forming the l-DOPA:Fe complex. Siderophore-like catechol compounds are known to bind siderocalin (Scn)/lipocalin-2 to form stable siderophore:Fe:Scn complexes. Scn is up-regulated in the substantia nigra of PD patients and may play a role in the pathophysiology of PD.

Their results demonstrate that L-DOPA forms a stable complex with Scn in the presence of Fe3+.

Expressed more simply, this means that L-dopa and the protein siderocalin combine in the presence of iron to create a complex that can cause cellular iron overload, resulting in an imbalance between free radicals and antioxidants, as well as neuroinflammation.

The authors speculate that as Parkinson's disease progresses, this effect increases, inducing these negative side effects, while the dose needed to relieve disease symptoms increases, resulting in a window narrow therapy.

It remains that the effects of the enzyme inhibitor used to mitigate L-Dopa side effects, are not trivial either, but this study does not address this subject.

Moreover L-Dopa is not a panacea either, indeed its therapeutic effectiveness is different for different types of symptoms. Bradykinesia and rigidity are the most sensitive symptoms to L-Dopa administration, while tremors are less sensitive. Speech disorders, speech and swallowing disorders, postural instability and frozen gait are the least reactive symptoms.

Is weight loss inevitable in ALS?

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Muscle wasting is one of the most striking symptoms of ALS. There were studies by Kasaskies and others, that demonstrated ALS patients have to ingest much more calories than comparable healthy persons. Our website has its own calorie calculator.

Johannes Dorst and colleagues from Ulm's university, conducted a randomised controlled study (Safety and Tolerability of Ultra-high-caloric Food Supplements in Amyotrophic Lateral Sclerosis (ALS); TOLCAL-ALS study) in 64 patients with possible, probable or definite ALS according to El Escorial criteria. Patients were randomised into four groups:

  • a high-caloric fatty supplement (405 kcal/day, 100% fat),
  • an ultra-high-caloric fatty supplement (810 kcal/day, 100% fat),
  • an ultra-high-caloric, carbohydrate-rich supplement (900 kcal/day, 49% carbohydrates)
  • an open control (OC) group without any supplement. The primary endpoint was tolerability. Patients were followed up over 4 weeks.

Gastrointestinal side effects were most frequent in the ultra-high-caloric fatty supplement group (75.0%), while loss of appetite was most frequent in the ultra-high-caloric, carbohydrate-rich supplement group (35.3%).

During intervention, patients gained +0.9 kg/month of body weight in the high-caloric fatty supplement group and the ultra-high-caloric fatty supplement group. Patients in the controlled group continued to lose body weight (−0.5 kg/month).

The findings suggest that high-caloric food supplements frequently cause mild to moderate tolerability issues in patients with ALS, most notably gastrointestinal symptoms in high-fat supplements, and loss of appetite in high-carbohydrate supplements. All three high-caloric food supplements tested are suited to increase body weight.

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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.

A non-invasive photooxygenation method for Alzheimer's disease

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Some neurodegenerative disorders are pathologically characterized by the deposition of abnormally aggregated proteins, both inside and outside the cells, in various peripheral tissues and the central nervous system (CNS). These diseases are called amyloidosis.

These amyloidogenic proteins are soluble in their healthy state. Yet under some unknown conditions, they can aggregate and form tertiary structures in crossed β sheets, ultimately leading to the onset of each disease. The pathological signs characteristic of Alzheimer's disease are two types of amyloid accumulation, each consisting of Aβ and tau.

Therefore, inhibition of amyloid protein aggregation or efficient clearance of already formed amyloids are considered promising therapeutic strategies. However, this strategy has so far been unsuccessful to improve cognition in Alzheimer's disease, so there is a need to investigate new ideas.

With the aim of treating Alzheimer's disease, scientists have studied the artificial addition of oxygen atoms to amyloid by a photooxygenation catalyst and photostimulation. enter image description here

Oxygenated Aβ has the ability to inhibit the aggregation and clearance of Aβ in the brain. It was clarified that the clearance of oxygenated Aβ was improved and that microglia are involved in the mechanism. Similar experiments were performed with special attention to astrocytes as cells other than microglia in the brain, but no effect of improving the clearance of oxygenated Aβ was observed. This suggests the specific involvement of microglia.

Scientists have also attempted to develop a non-invasive photooxygenation method with the aim of adapting this method to humans. After developing a new photooxygenation catalyst with cerebral migration properties and performing a non-invasive reaction of intravenous administration of the catalyst and light irradiation from outside the skull, Aβ was able to be oxygenated in the brain of a mouse. alive.

Tongue measurements and pharyngeal residue in amyotrophic lateral sclerosis.

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This study aimed to analyze the relationship of measurable characteristics of the tongue in patients with amyotrophic lateral sclerosis (ALS) and the accumulation of residue after swallowing in an area located just after the tongue. enter image description here This accumulation of residue provides a sensation of bolus stuck in the throat and increases the risk of weight loss, choking and pulmonary complications.

Twenty-one ALS patients were assessed for tongue pressure, tongue endurance, tongue thickness and residue after swallowing of the 10 ml of moderately thickened consistency. This study concluded that all tongue measurements were low in ALS patients with and without residue.

Therefore, these tongue measurements are not good predictors of vallecular residue in the tested volume and food consistency.

Read the original article on Pubmed

Entrepreneurial activism, mannitol and Parkinson's disease

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A new article in the journal BioSocieties, published by Drs. Shlomo Guzmen-Carmeli and David A. Rier, from the Department of Sociology and Anthropology at Bar-Ilan University, tell the story of CliniCrowd, an Israeli company established to test the effectiveness of nutritional supplements like mannitol, cinnamon or cherries in Parkinson's or Alzheimer's disease.

CliniCrowd's model emphasizes speed, efficiency and creativity in dealing with a particular kind of unfinished science, involving potential orphan drugs which, of natural origin, cannot be patented.

Indeed, scientific questions do not all have the same chances of being explored by officially accredited scientists.

The term “unfinished science” refers in sociology to areas of research identified by societal movements as having potentially important social impacts which are however not funded, or incomplete or even completely ignored. This research, although often initiated, is ultimately not carried out for financial, theoretical, ideological or even political reasons.

The classic model of Parsons (1951) of the patient's role as patient supposes that all the action lies with the doctor (the expert), who acts on the passive patients who themselves remain passive, because a priori incompetent.

However, this evolved towards the end of the 20th century, in particular with the fight against AIDS. In 1987, the Community Based Research Initiative, a partnership of physicians and community patients, began a pivotal clinical trial of a treatment for pneumocystis pneumonia, then the main threat to AIDS patients.

The trial provided important clinical data, quickly influenced clinical practice, and was even used by the United States Food and Drug Administration (FDA) in the approval process.

Activists have also formed groups to identify and obtain (sometimes, via smuggling) potential treatment not available in the United States. They criticized drug companies for their high prices and inability to study a wider range of compounds. They particularly attacked the FDA's reliance on very slow and expensive randomized clinical trials (the traditional “gold standard”).

In 2004, the PatientsLikeMe community site was started by two brothers and a friend of a patient with amyotrophic lateral sclerosis (ALS). It opened in 2006 as an online platform, allowing patients with ALS to share their downloaded and anonymized clinical data, assess their own progress, exchange advice and support. , and to contribute more generally to emerging clinical knowledge on the disease.

Finally, PatientsLikeMe is currently a for-profit company, as it was acquired in 2019 by a large healthcare management company. They sell aggregated and anonymized data to academic and professional customers such as pharmaceutical and medical device companies.

In Israel, defense elites and high-tech start-ups are often considered some of the brightest and most innovative in society, trained to think creatively, collaborate and take risks.

Dan Vesely, is a retired Israeli general and high tech entrepreneur. Here's how he describes his response to his terrifying Parkinson's diagnosis in 2013: "If there’s a problem, deal with it. No crying over spilled milk or grieving about my misfortune, about what I ‘won’ [said cynically]. Come on, what do we do next? We think of solutions. [interview, January 24, 2018]"

Vesely, obviously dissatisfied with the treatment options available to him, then turned to acquaintances for help. A small group of entrepreneurs have gathered around him to research the published research on Parkinson's disease.

They quickly noticed the published - and forgotten - study on the possible effect of mannitol on patients with Parkinson's disease. Vesely and some partners contacted Professor Dan Segal of Tel Aviv University, who had co-led the research team, and asked to meet with him:

"It had not yet been tested on humans. So I made an appointment .... Prof. Segal told us his story, described the experiment, and said it's all simply been shelved, there's no incentive for the pharmaceutical companies. at each other and said, 'So we'll take it!' The professor said, 'Who exactly are you? You brash Israelis, who are you?' But it was clear to us that if you can't go through the door , you go through the window. [Vesely interview, Jan. 24, 2018]"

The heartbreaking story of the abandonment of the study born affected the group of friends. Vesely then resolved to test the mannitol on himself. However, its partners dissuaded it from being ineffective for the community because it was totally inconclusive. Instead, together they decided to test mannitol on a number of patients with Parkinson's disease.

In the absence of the support of a pharmaceutical company ready to invest in clinical research, they then sought to test mannitol as if it were a military operation.

They adopted a model, marrying patient self-experimentation with crowdsourcing techniques. Inspired by similar crowdsourcing projects like PatientsLikeMe, the group then planned to create a website for patients with Parkinson's disease who would agree to take mannitol regularly for an extended period.

This alternative is not, however, a real substitute for “* classic *” clinical trials. The survey platform would indeed lack a control group and patient monitoring would be carried out on site on a voluntary and independent basis, and not by a doctor. Nevertheless, this survey platform would generate preliminary data to justify the need for more formal clinical research which would be a result of great value in itself.

The founders of CliniCrowd initially considered marketing mannitol directly, but decided not to, to avoid conflicts with their research. But the founders of CliniCrowd nonetheless chose to register it as a company rather than a non-profit organization. This reflected their primary motivation to “get the job done” as quickly and efficiently as possible, through entrepreneurial tactics, rather than adopting the identity and tactics of social activism. In addition, Israeli non-profit organizations are more regulated than commercial companies.

So they created the company in August 2016. They recruited qualified staff with experience in planning and conducting clinical trials to create the company's platform, and then started recruiting patients using patient forums and media exposure.

At the start of 2021, 2,480 patients had registered on the platform dedicated to the research of mannitol for Parkinson's disease. Of these, 1,364 (55%) had completed questionnaires more than once. The platform allows patients to record and track data related to their disease and (while maintaining anonymity) compare this data with that of other members of the community. It is also possible to share the stored data with the attending physician.

CliniCrowd's efforts have unfolded in several stages. As Parkinson's patients on the platform began taking mannitol and regularly filling out questionnaires about their symptoms, the next step was to attract accredited scientists to conduct larger trials.

CliniCrowd's initial data helped generate public pressure, which in turn led to a formal clinical study, launched in 2018 at the Hadassah Medical Center in Jerusalem. This study (https://clinicaltrials.gov/ct2/show/NCT03823638), conducted with public funding, examines the effects of mannitol on Parkinson's disease. As of June 2021, the study was continuing, but had slowed down somewhat due to the coronavirus and its severe impact on the medical system. Additional studies, at universities and medical centers in the UK and US, are expected to begin shortly. As far as the authors of this article are aware, at the time of writing, however, these are limited studies.

Nonetheless, there has already been a major shift in the way scientists view mannitol research. As Vesely, the patient-founder of CliniCrowd, noted:

"It gives me great satisfaction that the studies we are currently talking about [the clinical research underway in Jerusalem and expected further studies] would not have taken place, nor would they have received funding or the attention of the medical establishment and the public, without the buzz and especially the clinical indications that CliniCrowd achieved in the wake of the surveys. [interview, July 7, 2019"

Researchers involved in planning the clinical trial confirmed in interviews with the authors that without public pressure, it is unlikely that a trial would have been initiated.

In fact, CliniCrowd's position vis-à-vis the biomedical establishment has evolved over the course of its short history. In early interviews, founders sharply criticized the pharmaceutical industry. For example, in the first interview with CEO Amir Sadeh, he describes the decision to start the business as follows:

"The goal is to create something that cannot be ignored and make available to the public what the pharmaceutical companies are trying to hide from us. Because they [such 'ignored' compounds] do not generate income, they do not make a profit, so it's better not to know about them at all. But now we're exposing them, showing their nakedness in public, telling them it's inexpensive and accessible. It treats the cause rather than the symptoms, and that's why it's the worst thing for the pharmaceutical companies to find a solution to Parkinson's disease. Ten million people, five billion dollars a year — as far as they're concerned, let's just treat the symptoms. It's cynical but that's the way it is…. [T] he benefit of the patients is not the paramount interest of the companies or the doctors, because they are waiting for the next seminar in the Seychelles, courtesy of one company or another. [interview December 3, 2017]"

Yet this initial position of "rebels against the pharmaceutical industry" was created by elite members of the Israeli establishment,

With this approach, CliniCrowd obviously found it difficult to gain the trust and support of the medical establishment.

From interviews the authors conducted with patients who started taking mannitol between 2016 and 2018, it appears that those who saw their doctors have encountered substantial resistance to adopting mannitol as a remedy. The doctors' objections included comments such as, "this is a good woman's medicine" and "you had better get a rabbi's blessing."

At a conference of neurologists in early 2017, CliniCrowd delegates had only a few minutes to present their action, and most conference attendees ignored their speech. Such contempt is reminiscent of the opposition to the community production of knowledge about AIDS more than a generation ago.

The interviews clearly showed that the choice to adopt terms such as "dietary supplements" and "functional foods" reflects CliniCrowd's tactical decision to redefine mannitol as a new substance in the food supplement market.

Here's how CEO Sadeh described the change, in a follow-up interview: "We started out thinking we would call the venture Ampha, as opposed to Pharma. But the more we got into it, the more we realized that was not the point. Like Netflix doesn’t mean all movie theatres are closed, and Airbnb hasn’t replaced hotels, and Uber hasn’t replaced taxis, so CliniCrowd won’t replace the pharmaceutical companies. We fill a void and add something extra. If we started out by setting ourselves against the pharmaceutical companies, now we’re not against them, we’ll be in favour. We’ll complement them. Let’s shift the playing field. Instead of acting on the fiery and aggressive pharmaceutical playing field, let’s move the field elsewhere....And as long as the whole world of medicine doesn’t dance according to the interests of the pharmaceutical companies, we’ve done something great. [interview July 7, 2019]"

The rebranding of mannitol as a functional food proved to be a valuable maneuver, enabling CliniCrowd. This has helped promote acceptance of mannitol among physicians and patients.

Indeed, in the second half of 2018, the authors observed a change in attitude among doctors. Three doctors interviewed for the study told us that once they realized it was a dietary supplement, they stopped protesting: “It’s a dietary supplement. It may not help, but it is not harmful”.

As one neurologist explains: "I think no doctor likes it when the patient comes and says, 'Listen, I've found a treatment.' Most of the time I have to make sure his feet are on the ground, and I must explain why, most probably , in his case it won't work. This was also my initial response to mannitol, complete resistance, not wanting them to take it .... The attitude changes when there is already information and a mass of patients who have collated and documented its use in an orderly manner. Moreover, they didn't come and say this is a magic drug, but rather that it may help with some of the symptoms .... I suggest to patients, especially at the beginning, that they should read about mannitol. I definitely don't exclude it, in fact quite the opposite."

To understand how the patients themselves experienced this, consider Menachem [pseudonym], 68, diagnosed four years earlier. Asked about the experience of taking mannitol and participating in the online questionnaire, he replied: "My participation in the experiment has turned my world around. I come to the doctor and update him, see? I, Menachem, taught the neurologist that there is such a thing as mannitol, and that I am taking part in an experiment with other patients. When I go to see him, he immediately stands up! "Welcome", he says, "tell me how you are getting on". There is a sense that we are colleagues, and that I am doing something incredibly important. There is something in [mannitol] that helps, it’s not a magical cure, or maybe I no longer suffer. But there is an improvement in my sleep, my sense of smell, and also my difficulty in movement. [interview Oct. 30, 2019]"

Note the ease Menachem describes in his relationship with the doctor, his feeling of being an expert, his delight and agency he feels about being involved. These are all so important to him that he mentions them even before his improved health, which he attributes to taking mannitol on a regular basis.

In conclusion, CliniCrowd demonstrated a new way of approaching "* unfinished science *", using participatory research to generate public pressure and influence with which to formally attract scientists to test low potential compounds. profit. CliniCrowd represents an intersection of scientific knowledge, technologies, practices, it is also the product of a sustained process of dissemination and decentralization of expertise.

Clinical trials are not the right tool for testing drugs for chronic disease

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There are 500+ failed clinical trials for ALS and a staggering 2,000+ for Alzheimer. It's even worse for diabetes: There are 14,000+ failed clinical trials and we still have no cure in sight.

There is no scientific explanation for this phenomena. It is not even recognized as a problem.

In addition drug research on chronic diseases in mice translates rarely in humans. The cost is enormous for the society, again there is no explanation, and little motivation to improve this dire situation.

We must miss something huge.

I would discuss this on a philosophical level, particularly how we think about disease and health, and how it has straight consequences on the design of clinical trials.

In my understanding the notion that a drug should have effects in a few days or at least a few weeks, is deeply associated with communicable diseases. In our young age, we had fevers and in a few days it was all gone and we were back at the playground with as much energy as before.

Health is perceived as the "normal" situation.

Doctors have the same mindset: They want you to keep your blood work in the standardized values, specialists search for "anomalies" with imaging technologies.

For everyone in our societies health is the norm and diseases are only temporary deviations.

I argue that diseases are not temporary deviation to the norm.

Our bodies are constantly changing, even during illness, and there is no way to get healthy quickly. We lose capacities, organs atrophy or remodel. It is therefore unlikely that a return to health will be rapid.

Intuitively if you've had an illness for a few years, it will probably take a few years for you to regain your health. There is no magic pill, and it is a dangerous odyssey.

This why drugs work in mice and apparently not humans. When a mice model of disease heals in a month, the equivalent duration for humans is 3 years. No clinical trial tests drugs more than 6 months on the same patient.

This has dire consequences: As most clinical trials for chronic diseases last only a few months, they indeed fail to discover any significant improvement and we see that.

One way to improve this situation would be to change the goals of phases III and IV.

Phase III should have two goals: - Detect at least a minimal improvement in health. - Make sure the drug has nearly no side effects. Today side effects are minimized in clinical trials if there is no efficacious drugs. The idea is roughly that whatever improves the situation is desirable. This is perfectly correct if the uncomfortable time last only a few days, it is unacceptable if the side effects must be endured decades.

Phase IV should verify that the drug is indeed fully effective after a few years.

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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.

ALS is not just a disease of the primary motor area of the brain.

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Amyotrophic lateral sclerosis (ALS) is a rapidly progressive neurodegenerative disease with a median survival of 26 months after diagnosis. It usually affects older adults and is characterized by progressive weakness in the muscles of the limbs and difficulty speaking and swallowing.

Also and to differentiate this disease from other diseases with similar symptoms, for over a century ALS has been defined as a disease of the higher motor neurons. However, this definition is artificial in that for most of these 100 years it has been impossible to directly verify the state of upper motor neurons in patients.

The very great diversity of symptoms has led "theoretical" doctors to introduce new pathologies (PLS, PMA, MMA, PLS, PBP) which seem very far from clinical reality.

Finger and foot tapping scores have long been used as a surrogate for upper motor neuronal dysfunction in ALS studies. Myography studies are also very subjective.

Moreover, a minority of scientists do not share this point of view and prefer a hypothesis called "dying backward" where the disease begins either in a muscle or at the muscle / lower motor neuron junction, which is found in the peripheral nervous system. .

For the past fifteen years, scientists have recognized that frontotemporal dementia (FTD) is present in about 10% of patients at the time of diagnosis, with up to 50% of patients showing cognitive and behavioral deficits on detailed neuropsychometric tests. Frontotemporal dementia also has molecular characteristics similar to the majority of cases of ALS.

Fortunately, more and more doctors and scientists are using medical imaging to examine patients with neurodegenerative diseases. Functional MRI studies have demonstrated reduced cortical activity in the prefrontal cortices during voluntary movement tasks in patients with ALS. This indicates that the classic definition of ALS, as only a disease of the higher motor neurons, is wrong. Obviously the new imaging techniques are not well received by classical neurologists. enter image description here

Motor weakness associated with volitional tasks in ALS is associated with failures and compensations in larger networks and not with isolated dysfunctions in the primary motor area where the body of higher motor neurons is located.

However previous functional MRI studies were limited by small sample sizes (n <20) and the majority of studies either examined gray matter only with T1-weighted images, or white matter with diffusion tensor imaging ( DTI). So far, only four studies have included more than 20 ALS patients with a multimodal MRI protocol to study progressive whole brain changes, although none have included more than 35 ALS patients. Two of these studies demonstrated progressive changes in the corticospinal tract and found no change in gray matter after 6 to 8 months (Cardenas-Blanco et al., 2016; de Albuquerque et al., 2017). In contrast, generalized gray matter degeneration was reported with limited white matter involvement in the other two studies (Bede and Hardiman, 2018; Menke et al., 2014). More comprehensive analyzes were therefore necessary.

Texture analysis is a computer image processing technique that quantifies the variations and relationships between the intensities of voxels in an image, variations that are difficult to detect by qualitative visual inspection and may not be detectable by the methods. common image analysis

Two-dimensional (2D) texture analysis methods have been widely used in other neurological conditions such as brain tumors, stroke, epilepsy, and multiple sclerosis to detect and classify lesions. Scientists have developed an analysis of the texture characteristics of the whole brain (Maani, Yang & Kalra, 2015).

With this technique, the authors of a new article have shown that the autocorrelation calculated from T1-weighted images is altered in ALS compared to controls in the regions of the motor cortex, the frontal lobe. , temporal lobe and posterior limb internal capsule (PLIC).

A comprehensive assessment of progressive brain degeneration in ALS is essential to further understanding the pathophysiology of the disease. As such, the main objectives of this new study were (1) to examine brain changes in patients with ALS over an 8-month period with texture analysis of T1-weighted images, and (2) to assess whether the gradual changes are different between patients at slow and rapid evolution.

The study design included whole brain and region of interest (ROI) based approaches to study changes in texture. The authors hypothesized that

  • (1) texture alterations in T1-weighted images are present in gray and white matter and associated with the known pathology and clinical alteration of ALS;
  • (2) progressive brain degeneration is evident as texture alterations over time;
  • (3) gradual brain changes in rapidly progressing patients are more important than changes in slowly progressing patients.

To test their hypotheses, they conducted the study in a large multicenter cohort of 256 participants (119 controls and 137 patients with ALS). The mean age of the ALS patients was higher than that of the controls (p = 0.02) and there were proportionally more men than women in the ALS group than in the control group.

In the whole-brain group comparison, patients with ALS had reduced autocorrelation compared to controls in bilateral pre-central gyri, subcortical white matter, left supplemental motor area, left upper and middle frontal gyri, bilateral frontal white matter, bilateral insular cortex and bilateral temporal white matter.

Compared to controls, the slowly progressing ALS group had alterations in autocorrelation in bilateral precentral gyri, left middle frontal gyrus, bilateral frontal white matter, left insular cortex, and bilateral pyramidal tracts. In contrast, the rapidly progressing ALS group had fewer regions of altered autocorrelation in the frontal cortex, but greater involvement of bilateral pyramidal tracts, temporal white matter, and parahippocampal regions.

Conclusion: In this study, the authors set out to investigate progressive brain degeneration in ALS with texture analysis of T1-weighted images in a large multicenter cohort. they first showed that the texture abnormalities in the gray and white matter at the start were spatially congruent with the brain pathology of ALS.

It is important to note that textural alterations in the pyramidal tract have also been shown to be highly specific for clinical dysfunction of the upper motor neurons. This contrasted with the ALSFRS-R and finger and foot tapping scores which showed diffuse associations with gray and white matter structures. In addition, longitudinal analyzes revealed that the progression of gray matter was characterized by the spread of the pathology to the frontotemporal regions.

They observed progressive changes in the pyramidal tracts after only 4.5 months. This is a new and important observation because clinical dysfunction of the upper motor neurons did not progress during this period. Finally, they showed that progressive brain degeneration in ALS was based on the rate of disease progression at baseline. Taken together, these results also strongly suggest that texture analysis of T1-weighted images is a sensitive marker for longitudinal mapping of disease-related brain degeneration in ALS.

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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.

Deep sleep may slow the progression of Parkinson's disease

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In people with Parkinson's disease, dementia with Lewy bodies, and even other neurodegenerative diseases, slower, deeper sleep is associated with better cognitive performance and slower motor progression over time.

Yet, these patients have very serious sleep problems. They often take a nap intermittently, which fails to address the phase of deeper, more restorative slow wave sleep in which waste disposal speeds up in the brain as demonstrated in several previous studies.

More recently, scientists have begun to understand that slow wave sleep abnormalities also affect people with Parkinson's disease (Schreiner et al., 2021). Could their slow wave sleep disruption be similarly related, to the major protein aggregates of PD and their clearance?

The main finding of a new study is indeed that the modulation of slow waves in sleep influences neuropathological outcomes in two different mouse models of synucleinopathy. http://www.ncbi.nlm.nih.gov/pubmed/34878820

The study showed less synuclein buildup after improving slow waves with sodium oxybate compared to placebo, while sleep deprivation had the opposite effect.

The scientists used mice deficient in the vesicular monoamine transporter of dopamine transport protein 2 (VMAT2). Without VMAT2, dopamine builds up and damages neurons, causing α-synuclein aggregation, loss of motor function. and sleep disturbances.

They implanted an electroencephalography / electromyography machine in the skulls of young mice to track their sleep over 24 hours. Animals deficient in VMAT2 actually spent more time awake, with less REM and non-REM sleep, than their wild-type siblings.

What about old mice? As the aged mice deficient in VMAT2 did not tolerate the EEG / EMG implantation procedure, the scientists were therefore unable to analyze their sleep. Instead, they did it on 14 month old wild type mice.

They either sedated them with sodium oxybate, a narcolepsy drug, or kept them awake by placing them on a small platform over water for 16 hours. During 24 hours of EEG / EMG recording in each condition, mice that took sodium oxybate had slower waves during non-REM sleep, while sleep-deprived animals had shallower waves and less depth. more fragmented non-REM sleep.

Well-rested mice had less phosphorylated synuclein and less aggregates than controls, while the reverse was true in sleepless mice.

In addition, the researchers gave sodium oxybate to 5.5-month-old A53T mice (another animal model of Parkinson), which carry mutant human α-synuclein and develop Lewy body-like synuclein aggregates.

The drug increased clearance of α-synuclein aggregates so well that the western spots of their mesencephalic tissue almost looked like wild-type ones. "I thought it was fascinating that sleep so drastically alters the pathology in mice genetically intended to accumulate synuclein," Schreiner said.

Morawska et al. have also added a sleep deprivation arm using the platform over water method. They found that, in general, sleep deprivation increased synuclein aggregation, while improvement in SWS reduced it. However, it is difficult to directly compare the methods of sleep deprivation and improvement, as one is pharmacological (oxybate) and the other behavioral, and potentially stressful.

These results are consistent with previous studies on the link between slow sleep and pathological protein accumulation in Alzheimer's disease and imply that similar mechanisms may be present in synucleinopathies such as Parkinson's disease.

The present study is exciting because it provides more rationale to further explore the role and therapeutic potential of sleep, particularly slow-wave sleep, in clinical populations with neurodegenerative disorders, including synucleinopathies.

This is of interest because there are highly specific pharmacological and emerging non-pharmacological methods to improve sleep on the in humans.

Even so, the change in sleep in mice may not translate directly to humans, as humans and rodents have different stages of sleep (Matsumoto & Tsunematsu, 2021). Scientists are also uncertain whether sodium oxybate affects the neuropathology of people with Parkinson's disease.

It is a paper that complements for synucleinopathies what previous articles by Kang and colleagues (Kang et al., 2009) and Holth and colleagues (Holth et al., 2019) have done for amyloid and protein tau, respectively.

It is likely that for an intervention to be effective in patients, it will need to be given over the long term, and possibly to neurologically asymptomatic patients, and it is not certain whether sodium oxybate will work given the its propensity to cause side effects in the elderly adults.

In addition, we lack excellent biomarker readings for the burden of synuclein pathology in humans, so hampering clinical trials.

In their next study the researchers will use auditory stimulation by playing certain tones during slow sleep to try to specifically improve or decrease these brain waves in mouse models of Alzheimer's and Parkinson's disease.


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