I am pleased that two new articles bear a similar message: That neurodegenerative diseases can't be understood with the paradigm acquired with communicable diseases.

This paradigm tells us that as the pathogen is quite homogeneous, so is the disease phenotype. This is indeed wrong for non-communicable diseases like cancers and is even wrong for some communicable diseases like COVID-19 where the pathogens have heavily mutated.

One of these articles is "Serena Verdi et al, Personalizing progressive changes to brain structure in Alzheimer's disease using normative modeling".

The authors looked at 3233 brain scans. The number of non-standard brain structures increased over time in people with Alzheimer's disease. Patterns of change in outliers varied markedly between individual patients with Alzheimer's disease.

The authors say: "I think we need to pivot towards a new way of thinking to get away from the idea that this (brain) area is important, this area isn't". The big picture and the individual variability contained within it, is what counts.". Some of this individual variability may stem from the fact that many people with Alzheimer's have more than one cause of cognitive illness.

This idea that "we need to pivot towards a new way of thinking to get away from the idea that this (brain) area is important, this area isn't" is certainly important when we think of other neurodegenerative diseases such as ALS or Parkinson's disease.

Our knowledge about Parkinson's disease is limited. The official narrative is that Parkinson's disease is characterized by progressively expanding nerve cell death originating in substantia nigra, a midbrain region that supplies dopamine to the basal ganglia, a system involved in voluntary motor control. The cause of this cell death is poorly understood but involves alpha-synuclein aggregation into Lewy bodies within the neurons. Substantia nigra is really a tiny part of the brain, and other studies have already revealed a wider involvement in the brain. I guess we would make significant progresses in the disease knowledge if we acknowledge that if alpha-synuclein is involved in Parkinson's disease, it is unlikely its effects are limited to a tiny portion of the brain, as alpha-synuclein is abundant in the brain, while smaller amounts are found in the heart, muscle and other tissues and Lewy bodies are in the midbrain and the cortex.

Another interesting article is: "Ophthalmate is a new regulator of motor functions via CaSR: implications for movement disorders".

While the official narrative is that Parkinson's disease is characterized by neuronal death in substantia nigra, which supplies dopamine to the basal ganglia, a system involved in voluntary motor control, it has been known for decades that robust motor activity can happen in Parkinson's mouse models when L-DOPA conversion to dopamine is blocked! The motor improvement is larger than in the conventional case where L-DOPA is metabolized in dopamine. The authors hypothesized that there was an alternative pathway or mechanism, independent of dopamine signaling.

The authors sought to determine the metabolites associated with the pronounced hyperactivity observed. They observed that the peak in motor activity induced by inhibiting L-DOPA conversion into dopamine in Parkinson’s disease mice was associated with a surge (20-fold) in brain levels of the tripeptide ophthalmic acid (also known as ophthalmate in its anionic form). When they administered ophthalmate directly into mice's brains, it rescued motor deficit in a dose-dependent manner.

The team investigated the molecular mechanisms underlying ophthalmate’s action and discovered, that ophthalmate binds to and activates the calcium-sensing receptor (CaSR). To strengthen their findings, they verified that a CaSR antagonist inhibits the motor-enhancing effects of ophthalmate.

A link between Parkinson's disease and the calcium-Sensing Receptor is interesting as CaSR also Mediates β-Amyloid production. There is only one other publication that explicitly links the disease to CaSR. Calcium acts in a number of signal transduction pathways as second messengers, so maybe it is not wise to read too much about a link between Parkinson's disease and CaSR, but finding that lack of dopamine is not the main cause of Parkinson's disease, is a major finding.

Vitamin B12 injections are sometimes proposed by neurologists to ALS patients. Patients often decide to start the treatment because of the perceived low risk of side effects and the potential benefit to their quality of life. It is typically shipped as a sealed frozen package with several vials containing a 25-mg injectable dose. Patients are typically advised to inject 50 mg of B12 daily, which is 100 times the daily recommended dose. Usually, ALS patients recognize some benefits from the injections, such as increased energy, reduced fatigue, and improved balance. However, the high cost of injection, lack of insurance coverage, and inconsistent syringes are significant challenges faced by patients.

High-dose methylcobalamin treatment involves intramuscular injection of 25mg to 50mg of methylcobalamin twice a week, which is 50 to 100 times the dose of existing drug injections.

A phase II/III clinical trial for ALS patients was started in Japan, and the results were published in 2019. 373 ALS patients who had been onset for less than 3 years were recruited for a methylcobalamin clinical trial with three branches where patients have daily administrated 50mg, 25mg, or a placebo. It was conducted over 3.5 years. As a result, the methylcobalamin group showed a tendency to show better results in terms of the decline in ALSFRS-R, but the difference was not significant, and overall efficacy could not be demonstrated to Japanese authorities.

However, when a subanalysis was conducted only for patients who were enrolled within 12 months of onset (close to diagnostic), the 50 mg group, the 25 mg group, and the placebo group showed less decline in ALSFRS-R and a longer time to the primary endpoint. Post-analysis is frowned on because in small groups there are always statistical flukes and it's easy to cherry-pick some of these to prove whatever. But here the size of the trial was a bit larger than usual so there was more confidence in the findings.

The difference in decline in ALSFRS-R between the 50 mg group and the placebo group was statistically significant. Based on these results, a clinical trial (JETALS trial) was conducted in 2017 to confirm the reproducibility of the subanalysis, and the results were announced in May 2022. Results were reported on this blog.

In the JETALS study, 130 ALS patients within 12 months of onset were recruited and assigned to a twice-weekly 50 mg group or a placebo group. As a result, the reduction in ALSFRS-R score at 16 weeks was −2.66 in the methylcobalamin 50 mg group and −4.63 in the placebo group, which was significantly better in the active drug group.

There was no difference in side effects of the drug between placebo or methylcobalamin-treated participants. There was a marked reduction in serum homocysteine levels. Homocysteine is neurotoxic and has been associated with ALS cases but also with Alzheimer's and Parkinson's diseases. It may be a byproduct of methionine metabolism and there are a few studies that discuss the influence of diet on homocysteine via methionine in diet. High levels of methionine can be found in eggs, meat, and fish; sesame seeds, Brazil nuts.

These results are better than most previous drug results in ALS, but indeed it does not stop the disease progression. Based on these results, it was announced in January 2024 that a new drug application for methylcobalamin had been submitted in Japan.

Eisai Co. announced last week that it has obtained manufacturing and marketing authorization approval for amyotrophic lateral sclerosis (ALS) treatment “Rozebalamin® for Injection 25 mg” (mecobalamin) in Japan as a treatment for slowing progression of functional impairment in amyotrophic lateral sclerosis.

It should be noted that although there were statistically significant reductions in ALSFRS-R, other measures such as muscle strength, forced vital capacity, and the ALSAQ-40 total score, were not changed. This is a bit confusing as ALSFRS-R and ALSAQ-40 while not identical are similar enough, ALSAQ-40 adds a well-being dimension to the usual questionnaire. How could ALSFRS-R show an improvement if it's not reflected in ALSAQ-40?

As UK's Alsa-Mnd remarks, as the drug was only tested on participants early in the disease process, it is unclear if the treatment would be appropriate for participants with more advanced diseases.

In addition, Alsa-Mnd says it may not have been a truly blinded trial as methylcobalamin treatment results in a marked change in urine color which could mean that participants may have known whether they were receiving a placebo or methylcobalamin, and that could have influenced results (including a potential “nocebo” effect). This is supported by the fact that the placebo group appeared to worsen their rate of disease progression once the trial commenced.

It's possible that regulation agencies are afraid of the considerable political pressure from patient organizations who accuse them of being inactive, and that as for Alzheimer's disease and (temporarily) for AMX0035/Relyvrio they prefer to authorize new drugs even if they are ineffective, instead of waiting decades for an effective drug.

Here is a somewhat interesting article about Alzheimer's disease, but I guess it has also value for studies of ALS and Parkinson's disease.

Until the 1980' all cells in the brain that were big enough to be studied routinely were the neurons. Neurons are impressive cells because they are extremely long. The other cells were called the glue "glia" because they had no obvious functions. Neurons are also impressive because they can convey electrical and chemical signals over long distances. Neurons once mature, mostly do not divide, especially the ones with long axons. Other cells more conventionally divide every few days. Those other cells, which compose half of the brain's cells, are receiving more attention. There are multiple types but normally they are there to assist neurons in their task. A simplified view tells that neurons are a sort of plumbing system and the glial cells are the real actors in the brain.

One of the glial cells, the astrocytes, seems to play important roles, and these roles may change depending on biological events such as stress or pathogen intrusion. When they enter the state called reactive state (M1), they kill neurons, in a similar manner that macrophages (white cells) kill infected cells.

In Alzheimer's disease, the shrinking of the brain which is the result of dying neurons and glia, is associated with aggregates of amyloïd proteins (Aβ). The study found that Aβ protein triggers autophagy in astrocytes. Autophagy is a cellular process involved in waste removal and recycling. Cells need new proteins every passing minute to function correctly, and the diet would never be able to provide protein building blocks at the required speed, so it is of the utmost importance for cells to recycle used proteins. There are several kinds of autophagy mechanisms in cells. Neurons being quite passive giant cells, autophagy is mostly assured by astrocytes.

Recycling proteins is not a clean job, it involves breaking proteins into smaller components (the metabolites or even amino acids) in a series of steps. Some of these intermediate components are toxic.

This article investigates the role of autophagy in astrocytes in the context of Alzheimer's disease (AD). Autophagy plays a crucial role in clearing Aβ so disrupting autophagy in astrocytes leads to increased Aβ plaques and cognitive decline in AD mouse models. Conversely, enhancing autophagy by over-expressing the LC3B pathway with a genetic therapy in astrocytes can reduce Aβ plaques and improve cognitive function.

It is believed by the authors that Aβ is toxic because it induces urea cycle activation in astrocyte as a compensatory mechanism to deal with the toxic effects of Aβ.. The urea cycle is a metabolic pathway that primarily occurs in the liver, but it can also be active in astrocytes. This pathway is involved in detoxifying ammonia, a toxic byproduct of amino acid metabolism.

Overall, this study provides evidence that targeting autophagy in astrocytes may be a promising therapeutic approach for AD. Understanding the relationship between Aβ, autophagy, and the urea cycle could potentially lead to new therapeutic strategies for AD. For example, targeting the urea cycle or autophagy pathways might be explored as potential approaches to reduce Aβ toxicity.

As loving standards progressed during the last century, the diet became richer, and health conditions, such as gout, which were usually associated with people with high living standards became increasingly more common. It was soon recognized that acid uric imbalance was associated, not only with gout, but with a range of diseases. Most striking associations are inverse correlations as they should teach us something. One such inverse correlation is between elevated acid uric levels and Parkinson's disease. On the contrary, there is an association between low levels of acid uric and patients with Parkinson's disease, or multiple sclerosis. Yet something related to Parkinson's disease may cause low uric acid (reverse causation). Indeed, Parkinson’s disease is characterized by the loss of dopaminergic neurons in the substantia nigra pars compacta and the presence of Lewy bodies and Lewy neurites, which mainly consist of aggregates of α-synuclein. It is believed that α-synuclein aggregates poison the brain's cells and indeed especially this tiny part of the brain named "substantia nigra". Yet like other protein aggregates, they may form to protect the brain against some external aggression or stressing event. So the biological mechanisms underlying α-synuclein relationships with dopaminergic neurons have never been firmly established.

While the most frequently proposed mechanism for uric acid's inverse association with Parkinson's disease is that it is an antioxidant, however, clinical trials aiming to raise uric acid levels failed to slow the progression of Parkinson's disease. Then some scientists argued that many studies have pointed to mitochondrial dysfunction in Parkinson's disease. One of the major functions of mitochondria is producing energy in the form of ATP, which is quantitatively the most abundant of all purines in the body. As serum uric acid is a by-product of purine metabolism, mitochondrial dysfunction, and energy failure in Parkinson's disease may lead to low serum uric acid levels. An excellent review can be found here.

There is ample evidence that neurons can internalize extracellular aggregates by endocytosis. Some studies have shown that acid uric inhibits α-syn endocytosis by neurons thereby limiting the progression of the disease.

To precise the relation between Parkinson's disease and uric acid, a study shows that factors other than the purine metabolic system might influence CSF values of uric acid and that purine recycling pathways may be impaired. enter link description here

The current study found a significant reduction in hypoxanthine and inosine levels in the CSF of patients with PD but not in the serum. This small study, published in Nature Parkinson's Disease Journal, was published in preprints last year. Basically, it confirms previous findings such as those reported in the 2023 review above.

If our readers do not belong to academic or pharmaceutical circles, they certainly think that rationality guides the choice of drugs tested in clinical trials. They also certainly think a drug is tested in a clinical trial only if pre-clinical works show a strong signal of efficacy in the targeted disease.

We live in a human, imperfect world, but sometimes it borders on stupidity. Let's discuss the case of memantine. It's a drug that has been known for 60 years. It was bizarrely applied to a large variety of mostly unrelated diseases, like diabetes, OCD, autism, depression, Parkinson's, and Alzheimer's diseases as well as COVID-19.

In all these cases it had consistently shown it was ineffective. If one is especially interested in ALS, it's interesting to note that there is no published preclinical work on memantine in ALS.

Yet there were 5 clinical trials of memantine in ALS!

The latest had just published its results/ Two of them were phase III clinical trials, the others were phase II, so it cost probably $50M overall.

What is behind this strange behavior? Are we so irrational as a species to make repetitively so impressively huge mistakes?

One layperson may be troubled to learn that in ALS only, there were more than 500 unsuccessful clinical trials.

Every week academics are claiming to have made breakthroughs in neurodegenerative diseases. Obviously, most if not all of these claims were wrong.

It seems that academic and pharmaceutical scientists are just throwing spaghetti at the wall to see if it sticks. Most of them are paid well at the end of the month for doing crappy work, so why bother working harder?

Jean-Pierre Le Rouzic (my email is at the bottom of the page)

A new study explores the evolving therapeutic landscape for Parkinson's disease (PD), emphasizing the growing interest in complementary therapies, particularly dance. While it's specific to one culture, I think we could use it in any culture, as long as physical therapy is done in a pleasant social setting. Here the authors report that the enjoyment factor associated with Garba dance likely contributed to better adherence to the treatment. Patients reported having fun, which is crucial for long-term engagement with any form of physical therapy.

Overview of Parkinson's Disease Treatment The primary treatment for Parkinson's disease is dopamine replacement therapy, which targets motor symptoms. However, as the disease progresses, the effectiveness of these medications diminishes, and patients often experience more pronounced nonmotor symptoms, including cognitive decline, mood disorders, and sleep disturbances. These nonmotor symptoms are particularly resistant to pharmacological treatments and negatively impact quality of life. In addition, dopamine replacement therapies create new mental (hallucinations) and physical challenges (cardiac fibrosis).

To address these challenges, a multidisciplinary approach involving surgery, physical therapy, occupational therapy, and cognitive interventions is often necessary. Yet, adherence to such therapies can be challenging, particularly among older adults.

Complementary Therapies for Parkinson's Disease Various complementary activities like dance, music, theatre, art, and Tai Chi have been studied as potential therapeutic options in recent years. Though evidence supporting these therapies is still in its early stages, initial findings suggest that they may positively affect nonmotor symptoms, psychological well-being, and overall quality of life. For example, music therapy has been reported to benefit motor and nonmotor symptoms, cognition, and emotional health. Similarly, active theatre therapy may help patients develop social and emotional skills in a supportive environment, potentially reducing depression and social stigma. Tai Chi has shown promise in improving balance and reducing the frequency of falls in patients.

Dance Therapy in Parkinson's Disease Among complementary therapies, dance has garnered significant attention for its potential to manage both motor and nonmotor symptoms of Parkinson's disease. Studies suggest that dance may enhance cognitive function, improve motor skills, and even increase dopamine release in the brain. Furthermore, the enjoyment and social aspects of dance make it an appealing form of physical activity, potentially enhancing treatment adherence. Various dance forms, including Irish set dancing, Argentine tango, and ballroom dances like the Waltz and Foxtrot, have been shown to improve balance, gait, and locomotion in Parkinson's patients, particularly in Western contexts. In India, traditional dances like Bharatnatyam and Kathak have been explored for their therapeutic potential, although their complexity makes them less accessible to all patients.

Pilot Study: Garba Dance as a Therapy for Parkinson's Disease The pilot study evaluated Garba, a popular Indian dance form, as a therapeutic intervention for Parkinson's disease. Garba involves relatively simple movements, making it more accessible than other Indian dance forms. The study assessed the effects of Garba dance on motor and nonmotor symptoms, cognitive functions, and mood. The results were promising, particularly in terms of improvements in motor symptoms, as measured by the Unified Parkinson's Disease Rating Scale (UPDRS). To say it in a few words, symptoms went from severe to moderate in 12 weeks. There were three groups, one practicing Garba dance, the other physical therapy, and the last one was the control. All groups took their medications. Obviously, it was not possible to make a fully blinded test where patients ignore which drug they are administrated. Still, UPDRS raters were blinded to treatment allocations at all time points in the study.

The UPDRS encompasses different aspects of the disease, it ranges from 0 to 260 but a value below 30 usually means a mild disease. All patients had a score of 35 at the beginning of the study, indeed severely disabled patients would not be able to participate in this study.

Motor Symptom Improvement: Patients in the Garba dance group experienced significant improvements in UPDRS scores after 12 weeks (going from ~35 to ~20), surpassing those in the physical therapy and control groups. The physical therapy group went from ~36 to ~30, while the situation worsened for the control group (~35 to ~37).

Mood and Sleep Benefits: Although the study found no significant improvement in nonmotor symptoms like activities of daily living (ADL) or cognition, it did observe improvements in mood and sleep. This is consistent with other studies that have linked dance therapy to enhanced emotional well-being and reduced depressive symptoms in Parkinson’s patients.

Limitations of the Study While the study results are encouraging, the authors acknowledge several limitations. The small sample size and short duration of the study prevent definitive conclusions. Additionally, there was no follow-up after the study to assess the persistence of the observed effects. The study also did not capture differences in motor symptoms during the "on" and "off" medication states, which could have provided more nuanced insights. Another concern was the incidence of near falls, though no actual falls were reported, likely due to the close monitoring of participants.

Implications for Future Research and Practice Despite its limitations, this pilot study suggests that Garba dance may be a viable complementary therapy for Parkinson's disease, particularly for patients with a cultural affinity for dance. The noticeable improvements in motor symptoms, mood, and sleep warrant further investigation in larger, more rigorous trials. The study supports the idea that enjoyable, culturally relevant therapies can enhance treatment adherence and improve the quality of life for Parkinson’s patients.

In conclusion, while Garba dance should not replace traditional physical therapies in India, it presents an additional option within a multidisciplinary treatment plan for managing mild-to-moderate Parkinson's disease.

**A new study claims that it observed that higher levels of soluble amyloid-β42, one of the main forms of amyloid-β associated with Alzheimer's disease, is associated with better cognition. Yet there is no description of a mechanism of action, this is just a correlation study. Source: Nephron via Wikipedia It is known that reduced CSF Aβ42 levels in Parkinson's disease and dementia with Lewy bodies predict cognitive impairment and a more aggressive disease course and correlate with postmortem β-amyloid plaques in the brain. Recently it was shown the same phenomenon also appears in Alzheimer's disease.

This article brings new insight in that it suggests that increasing the levels of CSF's Aβ42 with anti-Aβ monoclonal antibodies benefits Alzheimer's disease.

The authors analyzed data from 25,966 AD patients in 24 clinical trials of anti-Aβ drugs that either lowered or increased CSF Aβ42 levels. They focused on long-term (12 months or more) placebo-controlled trials of anti-Aβ drugs published up to November 2023. The scientists examined the effects of new anti-amyloid-β (Aβ) monoclonal antibodies on Alzheimer’s disease (AD). These antibodies are designed to reduce amyloid plaques in the brain, which are associated with AD. While their primary effect is to reduce amyloid in the brain, some also increase levels of the 42-amino acid isoform (Aβ42) in cerebrospinal fluid (CSF).

The study evaluated changes in cognitive function and clinical status and compared these changes with alterations in CSF Aβ42 and brain amyloid measured by PET imaging. Increased levels of CSF Aβ42 were associated with slower cognitive and clinical decline, as measured by ADAS-Cog and CDR-SB.

The authors hypothesized that normal, soluble Aβ42 in the brain is crucial for neuron health and that the loss of Aβ42, rather than the buildup of plaques, drives Alzheimer's, but it's not apparent in the article if this is verified.

Yet, as stated above there is no mechanism of action described, in my opinion, scientists focus too much on drugs using brute force. They seem to think only in terms of removing or more rarely increasing the level of some molecules, based on correlations, but not on complex descriptions involving multiple biological systems.

Another article from a university's public relations department claims that a major breakthrough has been made in Alzheimer's disease. There is one of these crazy articles every day. Source: Peta

This time, the bar is set very high by the public relations department: "Our research demonstrates that by targeting synaptic activity early, we may be able to prevent or slow the progression of Alzheimer's. This could revolutionize the way we approach treatment for this disease" noted Drs. Miranda Reed and Michael Gramlich.

Since Alzheimer's is characterized by significant loss of brain matter, we expect at least an article showing the genesis of new neurons in several model animals of different species. Showing a change in very different species gives hope that the action of a drug will be as effective on humans.

Alzheimer's disease scientists usually work on mouse models of the disease 3xTg mice that declare the disease at the age of 8 months. This age is convenient for academics to use the free labor of students, but in a human, it is about 25 years old. This is very young to model Alzheimer's disease.

But what makes me jump is that all that is measured by these scientists is the change in synapses in an in vitro culture of 3xTg mice!

In fact, using in-vitro culture of cells from an animal model is very convenient, no need to raise mice! But the odds this is translatable to humans are minuscule. Nobody does this in preclinical studies. The claims of a revolution in the treatment of human Alzheimer's patients are extremely ridiculous.

In addition, the names of authors Michael Gramlich and Miranda Reed appear in all sorts of publications, most of which have nothing to do with neurodegenerative diseases.

Additionally, one of the authors of this article is the CEO of Biohaven Pharmaceuticals. Another author is the Chief Medical Officer of this company, and while he is a medical doctor, he is also not an Alzheimer's specialist.