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.
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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.
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 WikipediaIt 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.
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.
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.
A great dream in neurodegenerative diseases is to regenerate the brain's cells. Alas, half of the brain's cells are neurons and they do not divide, except for a tiny portion of them which are located in a small structure deep in the brain.
Neurogenesis is most active during embryonic development and is responsible for producing all the various types of neurons of the organism, but it continues throughout adult life in a variety of organisms. Once born, neurons do not divide (mitosis), and many will live the lifespan, except under pathogenic circumstances.
In humans, adult neurogenesis has been shown to occur at low levels compared with development, and in only three regions of the brain: the adult subventricular zone (olfactory sense) of the lateral ventricles, the amygdala emotion, socialization) and the dentate gyrus of the hippocampus (inhibition of impulses, episodic memory, and spatial cognition). Neurogenesis in the human hippocampus decreases sharply after the first years. The hippocampus is a neural structure located deep inside the medial temporal lobe of the brain. It has a distinctive, curved shape that has been likened to the sea horse.
Prior research has demonstrated that there are conditions which increase the rate of neurogenesis, such as voluntary running or pharmacological treatment with memantine. On the contrary, conditions that decrease neurogenesis, such as natural aging or pharmacological treatment, have been shown to increase the expression density of perineuronal nets in the hippocampus's CA1 area. Perineuronal nets (PNNs) are extracellular matrix structures that regulate the excitability and potential for plasticity of the cells they surround. So it seems (but everything is complicated in biology) that the more perineuronal nets means the less neurogenesis.
Aerobic exercise has been shown to modulate short-term cognitive performance and long-term cognitive outcomes in many ways. In particular, running has been found to impact learning and memory ability in a timing-dependent manner.
Running before learning aids in the formation of new memories, yet, running after learning promotes the forgetting of recently acquired information!
One of the mechanisms that seems to contribute to this relationship between running and cognition is adult hippocampal neurogenesis, which increases with running. With increased neurogenesis, the excitability of the dentate gyrus changes, which has knock-on effects across the hippocampus.
Aerobic exercise has many effects on brain function, particularly in the hippocampus. Exercise has been shown to increase the rate of adult neurogenesis within the dentate gyrus and decrease the density of perineuronal nets in the hippocampus's CA1 area. The relationship between the rate of neurogenesis and the density of perineuronal nets in CA1 is robust; however, these studies only ever examined these effects across longer time scales, with running manipulations of 4 weeks or longer. With such long periods of manipulation, the precise temporal nature of the relationship between running-induced neurogenesis and reduced perineuronal net density in CA1 is unknown.
Here, the authors provided male and female mice with home cage access to running wheels for 0, 1, 2, or 4 weeks and quantified hippocampal neurogenesis and CA1 perineuronal net density. In doing so, the authors observed a 2-week delay before the increase in neurogenesis, coinciding with the delay before the decreased CA1 perineuronal net density. These results highlight the closely linked temporal relationship between running-induced neurogenesis and decreased perineuronal net expression in CA1.
If this article is about mice, one reader of this blog could speculate if running could improve the conditions of Alzheimer's or Parkinson's disease sufferers. Obviously it would be complicated to make those patients to run periodically. Most of them are disabled and some of them have nearly no physical activity. Maybe some adapted device like an exercise bike that is usable in a recumbent or lying position and under supervision by health professionals could be useful.
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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.
Two of them were phase III clinical trials, the others were phase II, so it cost probably $50M overall.
Source: Nephron via Wikipedia
Source: Peta
Running before learning aids in the formation of new memories, yet, running after learning promotes the forgetting of recently acquired information!