Since a long time there are competing hypotheses about ALS, does it start in the brain as a majority of scientists think, or does it start in a distal way as some talented scientists suggest?

Magnetic resonance imaging of the brain and cervical spinal cord is often performed in diagnostic evaluation of suspected motor neuron disease/amyotrophic lateral sclerosis. Anatomist90 via Wikipedia

Analysis of MRI-derived tissue damage metrics in a common domain facilitates group-level inferences on pathophysiology.

This approach was applied to address competing hypotheses of directionality of neurodegeneration, whether anterograde, cranio-caudal dying-forward from precentral gyrus (posterior frontal lobe of the brain) toward the cervical spinal cord, or dying-back with the disease progressing in the other direction.

In this cross-sectional study, MRI was performed on 75 Motor neuron disease patients and 13 healthy controls. MRI scans were reviewed by a consultant neuroradiologist to exclude significant confounding pathology.

Precentral gyral thickness was estimated from volumetric T1-weighted images using FreeSurfer, corticospinal tract fractional anisotropy from diffusion tensor imaging using FSL, and cross-sectional cervical cord area between C1-C8 levels using Spinal Cord Toolbox.

To analyse these multimodal data within a common domain, individual parameter estimates representing tissue damage at each corticospinal tract level were first converted to z-scores, referenced to healthy control norms.

Mixed-effects linear regression models were then fitted to these z-scores, with gradients hypothesized to represent directionality of neurodegeneration.

The results are a bit confusing, it seems that from C5, there is a forward propagation toward lower cervical vertebras, while above C1 there is a backward propagation toward precentral gyrus!

A major limitation of this study is that they only studied the brain and the upper part of the spinal cord. Upper motor neurons have their body in the motor area and extend to the junction with lower motor neurons (with eventually inter-neurons in between). The lowest corticospinal nerve they studied C8, contributes to the motor innervation of many of the muscles in the trunk and upper limb. Its primary function is the flexion of the fingers. So this study would be conclusive only if all patients had a bulbar pathology, yet only 17 patients on 75 had a bulbar onset.

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Il y a trois décennies, les scientifiques pensaient avoir percé le mystère médical de ce qui cause la maladie d'Alzheimer avec une idée connue sous le nom d'hypothèse de la cascade amyloïde. Dans cette hypothèse une protéine appelée bêta-amyloïde forme des plaques collantes et toxiques entre les neurones et font dépérir le cerveau. Les amyloïdes sont des agrégats de protéines, les amyloïdes sont connus pour provenir de nombreuses protéines différentes. Les raisons pour lesquelles l'amyloïde provoque des maladies ne sont toujours pas claires. Les plaques amyloïdes sont des dépôts extracellulaires de bêta-amyloïde. La bêta-amyloïde (Aβ) est une petite protéine qui est libérée à partir d'une protéine mère plus longue appelée protéine précurseur Aβ (APP). L'APP est produite par de nombreux types de cellules dans le corps, mais elle est particulièrement abondante dans les neurones.

L'hypothèse de la cascade amyloïde était simple et convaincante, et des décennies de travail et des milliards de dollars ont été investis dans le financement d'essais cliniques de dizaines de composés médicamenteux ciblant les plaques amyloïdes. Pourtant, presque aucun de ces essais n'a montré d'avantages significatifs pour les patients atteints de la maladie. Cela jusqu'en septembre 2022, lorsque les géants pharmaceutiques Biogen et Eisai ont annoncé que dans un essai clinique de phase 3, les patients prenant le médicament anti-amyloïde lecanemab présentaient une baisse de leur cognition de 27 % inférieure à celle des patients prenant un placebo.

Une lacune majeure dans les théories centrées sur l'amyloïde de la maladie d'Alzheimer est cependant que les fibrilles amyloïdes en soi ne sont pas toxiques, bien que le diagnostic de maladie d'Alzheimer est clairement corrélé à la densité des dépôts de bêta-amyloïde (Aβ).

Il y a des alternatives à l'hypothèse de la cascade amyloïde. De nombreux chercheurs ont pensé que la réponse pourrait résider dans les enchevêtrements Tau – des faisceaux anormaux de protéines à l'intérieur des neurones qui sont également caractéristiques de la maladie d'Alzheimer et encore plus étroitement liés aux symptômes cognitifs que les plaques amyloïdes. D'autres pensent qu'une activité immunitaire excessive ou mal placée pouvait enflammer et endommager les tissus nerveux délicats. D'autres encore ont suspecté des dysfonctionnements dans le métabolisme du cholestérol ou dans les mitochondries qui alimentent les neurones.

Des chercheurs ont développé un modèle mathématique expliquant en quoi les plaques amyloides seraient toxiques. Leur modèle a fait l'objet d'une pré-publication sur MedRxiv.

Le problème ne serait pas leur formation, mais plutôt leur destruction qui serait toxique. les scientifiques ont supposé que l'absorption cellulaire d'amyloïde est un facteur important définissant la toxicité de l'Aβ in vivo. Leur hypothèse est qu'en raison de l'intensité du renouvellement des protéines, les graines d'agrégation ne se forment pas dans le liquide interstitiel, mais apparaissent d'abord de manière intracellulaire à partir de l'Aβ endocytosé. Après avoir été exocytosées, ces graines se développent en agrégeant l'Aβ soluble et deviennent des plaques séniles.. Des idées similaires sont proposées depuis une vingtaine d'années. Source Merrill Sherman/Quanta Magazine

Dans ce modèle, les dommages cytotoxiques sont proportionnels à l'absorption cellulaire d'Aβ, tandis que la probabilité d'un diagnostic de maladie d'Alzheimer est définie par la cytotoxicité Aβ accumulée pendant la durée de la maladie.

Après absorption, Aβ est concentré par voie intralysosomale, favorisant la formation de germes de fibrillation à l'intérieur des cellules. Ces graines ne peuvent pas être digérées et sont soit accumulées de manière intracellulaire, soit exocytosées.

Aβ commence à s'agréger sur les graines extracellulaires et, par conséquent, sa concentration diminue dans le liquide interstitiel.

La dépendance de la toxicité et de l'agrégation de l'Aβ sur le même processus - l'absorption cellulaire de l'Aβ - explique la corrélation entre le diagnostic de maladie d'Alzheimer et la densité des agrégats amyloïdes dans le cerveau.

Les chercheurs ont testé leur modèle à l'aide de données cliniques obtenues auprès de l'Alzheimer's Disease Neuroimaging Initiative (ADNI), qui comprenait des enregistrements de la concentration de bêta-amyloïde dans le liquide céphalo-rachidien (CSF-Aβ42) et de la densité des dépôts de bêta-amyloïde mesurés à l'aide de la tomographie par émission de positrons. (ANIMAUX). Le modèle prédit la probabilité de diagnostic de maladie d'Alzheimer en fonction du CSF-Aβ42 et de la TEP et ajuste les données expérimentales au niveau de confiance de 95 %.

Cette étude montre que les données cliniques existantes permettent d'inférer des paramètres cinétiques décrivant le renouvellement de la bêta-amyloïde et la progression de la maladie. Chaque combinaison de valeurs CSF-Aβ42 et PET peut être utilisée pour calculer le taux d'absorption cellulaire de l'individu, la durée effective de la maladie et la toxicité accumulée. Ce modèle serait le premier à expliquer mécaniquement la corrélation négative entre la concentration d'Aβ42 dans le LCR et la probabilité d'un diagnostic de maladie d'Alzheimer.

We know that in ALS it is important to maintain the BMI at 27, which is incredibly difficult practically for patients but also psychologically for caregivers who do not understand that becoming mildly obese can be beneficial. This is especially true if the patient previously had a very healthy weight profile.

Several publications hint at similar benefits of weight gain in Parkinson's disease. Early weight loss is a typical symptom in Parkinson's disease patients and this may be accompanied by cognitive decline.

This observational study used data from the Parkinson’s Progression Markers Initiative cohort. The patients underwent annual non-motor assessments covering neuropsychiatric, sleep-related, and autonomic symptoms for up to 8 years of follow-up. Cognitive function was measured using the Montreal Cognitive Assessment (MoCA) and detailed neuropsychological testing. Linear mixed-effects models were applied to investigate the association of early weight change with longitudinal evolution of cognitive and other non-motor symptoms.

358 individuals with Parkinson's disease who had just received a diagnosis but had not yet begun taking medication for the condition were the subject of the study. They were 61 years old on average. 174 individuals free of Parkinson's disease were compared to them. While observational studies generally produce results similar to those conducted as randomized controlled trials, an observational study draws inferences from a sample to a population where the independent variable is not under the control of the researcher so it is possible there are some hidden bias in such studies.

A change in body weight of more than 3% during the study's first year was deemed to be either weight gain or loss. 98 individuals lost weight, 59 individuals gained weight, and 201 individuals maintained their weight.

Prior to the study's start and then once a year for up to eight years, participants took a test of their thinking abilities. They also looked for other non-motor symptoms, like anxiety, depression, and difficulty falling asleep, that Parkinson's patients might experience.

When compared to Parkinson's patients who maintained their weight, those who lost weight saw a decline in their scores annually. Fluency skills, showed the greatest decline in thinking abilities.

Conversely, Parkinson's patients who gained weight saw a slower decline in their processing speed test scores than those who kept their weight.

Weight change did not correlate with any other nonmotor symptoms.

There was no connection between weight change and results on the thinking skills test among individuals without Parkinson's disease.

According to Jun, "These results highlight the potential significance of weight management in the early stages of Parkinson's disease." If taking measures to prevent weight loss can slow cognitive deterioration in people with Parkinson's disease, more research is required to confirm this. ".

This observational study only demonstrates an association; it does not establish a causal relationship between weight changes and changes in thinking abilities. Yet diet change in order to gain weigth in a healthy manner is something that patients and carers can easily do at home.

Association of Early Weight Change With Cognitive Decline in Patients With Parkinson Disease

Body Mass Index, Abdominal Adiposity, and Incidence of Parkinson Disease in French Women From the E3N Cohort Study

Initial BMI and Weight Loss over Time Predict Mortality in Parkinson Disease

I dislike publishing about CRISPR technology or about ALS mice models yet the results in this article, if replicated, are amazing. It means that for 5% of ALS patients, there is an hope that a future drug might extend their survival by more than 12 years!

Although CRISPR-based gene-editing technology has received unreasonable hype, it represents a promising approach to providing genetic therapies for inherited disorders, including amyotrophic lateral sclerosis.

Toxic gain-of-function superoxide dismutase 1 (SOD1) mutations are responsible for approximatively 20% of familial Amyotrophic Lateral Sclerosis cases. This means 5% of all ALS cases.

Current clinical strategies to treat SOD1-Amyotrophic Lateral Sclerosis are designed to lower SOD1 levels, notably throught the use of ASOs. On October 17, 2021, a presentation of the phase 3 VALOR study indicating that Biogen's Tofersen did not demonstrate statistical significance in the primary measure of disease progression.

On June 3, 2022, additional 12-month open label extension data was presented, demonstrating a some positive effect for participants who received Tofersen early in their disease.

In this new publication, authors from Biogen used an AAV-gene therapy to deliver CRISPR guide RNAs designed to disrupt the human SOD1 transgene in SOD1 mice (huSOD1). Those transgenic mice express the human SOD1 gene, not the murine gene, so their disease is closer to the human disease than in other SOD1 mice models.

This intrathecal injection into neonatal huSOD1 mice caused robust and sustained mutant huSOD1 protein reduction in the cortex and spinal cord, and restored motor function.

Neonatal treatment also reduced spinal motor neuron loss, denervation at neuromuscular junction and muscle atrophy, diminished axonal damage and preserved compound muscle action potential throughout the lifespan of treated mice. SOD1 treated mice achieved significant disease-free survival, extending lifespan by more than 110 days. 110 days for a mice that can live 2 years is equivalent to 12 years for humans!

Yet this is not realistic for human patients, as even if we can detect patients at risk at neonatal stage, most of them will not develop ALS, and furthermore reducing their SOD1 level means they will be susceptible to the very diseases that this therapy tries to attenuate.

Importantly, a one-time intrathecal or intravenous injection of this therapy, immediately before symptom onset, also extended lifespan by at least 170 days.

The authors' approach also uncovered key parameters that resulted in improved efficacy compared to similar approaches and can also serve to accelerate drug target validation.

One question I have is why these technologies are not used to convert the mutated SOD1 gene into the normal wild-type SOD1 gene. This is important because living with reduced levels of SOD1 puts the patient at risk for neurodegeneration!

Let's hope this will lead to a full drug development program at Biogen. Yet there will be internal competition with the team in charge of Torfersen.

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Mouse models of neurodegenerative diseases have proven inadequate in translation into clinical research. There are several reasons, one of them is that in these animals the diseases progress at an extreme speed and the other is that mice and primates have quite different nervous systems. For example, in some cases, higher primates have direct connections between upper and lower motor neurons, whereas mice always have interneurons between upper and lower motor neurons. Source: Xocolatl via Wikipedia

The common marmoset, Callithrix jacchus, is increasingly being used as the preferred nonhuman primate model in biomedical research. Marmosets share several physiological and biological similarities with humans, and their use in research programs advances knowledge of several fields.

Mice diseases models are highly unrealistic, when transposed to humans it would mean that degeneration would appear at 20 years old! Due to the relatively shorter life span of 15 to 16 years and the smaller body size, studies conducted in marmosets may be more realistic. Since neurodegeneration is prevalent in aging humans, there has been much interest in the neurodegeneration of aging marmosets.

Their unique characteristics, such as small size, high fecundity, and rapid growth, offer additional advances in laboratory settings. This article reviews the developments in experimental disease models using marmosets based on authors' experience at the Central Institute for Experimental Animals in Japan.

The development of genetically modified marmoset models using advanced genome editing technology attracts researchers, particularly in neuroscience-related fields. In parallel, various marmoset models of human diseases induced by surgery or drug administration have contributed to preclinical and translational studies.

Among these are models:

• for Parkinson's disease, induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine;
• spinal cord injury models;
• a model for type 1 diabetes, induced by the combination of partial pancreatectomy and streptozotocin administration;
• a hepatic fibrosis model induced by thioacetamides.

The development of these models has been supported by refinements in veterinary care, such as the careful design of anesthetic protocols and better understanding of pathogenic microorganisms. In the second part of this review, the authors present a compilation of practices currently in use at at the Central Institute for Experimental Animals that provide optimal animal care and enable safe experimentation.

Indeed, most researchers will be reluctant to use marmosets. Diseases of mice models appear within a month, so the cost is low. No university lab would spend years before the results are available. If only for one thing, it would considerably slow down the pace of publications that condition the careers of scientists.

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Trends in digitalization suggest that older adults are increasingly familiar and comfortable with new technologies, and surveys from 2019 indicate that 77% of North Americans aged 50+ own a smartphone. In Sweden 66% of Sweden's older adults born during the 1940s use the Internet daily.

Mobile app-based tools have the potential to yield rapid, cost-effective, and sensitive measures for detecting dementia-related cognitive impairment in clinical and research settings. At the same time, there is a substantial need to validate these tools in real-life settings. The primary aim of this study was thus to evaluate the feasibility, validity, and reliability of mobile app-based tasks for assessing cognitive function in a population-based sample of older adults.

The authors of a new study employed two mobile app-based cognitive tasks building on recent findings on the functional brain architecture of episodic memory and the spatiotemporal progression of AD pathology. - First, the Mnemonic Discrimination Task for Objects and Scenes (MDT-OS), taxing pattern separation as a short-term memory task. Pattern separation is the process of discriminating among highly similar but unique pieces of information (e.g., where you parked your car today vs. yesterday).

• Second, the Object-In-Room Recall Task (ORR-LDR) was developed to tax pattern completion (29), i.e., the ability to retrieve a stored memory based on a cue of incomplete information. The ORR-LDR was implemented as a one- to three-day long-term delayed recall task, consequently assessing long-term memory.

A total of 172 non-demented older participants completed two mobile app-based memory tasks-the Mnemonic Discrimination Task for Objects and Scenes and the long-term delayed Object-In-Room Recall Task. To determine the validity of the tasks for measuring relevant cognitive functions in this population, the authors assessed relationships with conventional cognitive tests. In addition, psychometric properties, including test-retest reliability, and the participants' self-rated experience with mobile app-based cognitive tasks were assessed.

MDT-OS and ORR-LDR were weakly-to-moderately correlated with the Preclinical Alzheimer's Cognitive Composite and with several other measures of episodic memory, processing speed, and executive function. Test-retest reliability was poor-to-moderate for one single session but improved to moderate-to-good when using the average of two sessions.

The scientists observed no significant floor or ceiling effects nor effects of education or gender on task performance. Contextual factors such as distractions and screen size did not significantly affect task performance. Most participants deemed the tasks interesting, but many rated them as highly challenging. While several participants reported distractions during tasks, most could concentrate well.

However, there were difficulties in completing delayed recall tasks on time in this unsupervised and remote setting.

The authors' study proves the feasibility of mobile app-based cognitive assessments in a community sample of older adults, demonstrating its validity in relation to conventional cognitive measures and its reliability for repeated measurements over time. To further strengthen study adherence, future studies should implement additional measures to improve task completion on time.

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Andrographis paniculata, commonly known as creat or green chiretta, is an annual herbaceous plant widely cultivated in Southern and Southeastern Asia, where it has been believed to be a treatment for bacterial infections and some diseases. Andrographolide is the major constituent extracted from the leaves of the plant Source: J.M.Garg - Own work, via Wikipedia

Andrographolide is a labdane diterpenoid that has been isolated from the stem and leaves of Andrographis paniculata. Andrographolide is an extremely bitter substance.

Andrographolide has been studied for its effects on Alzheimer's Disease, Parkinson's disease, multiple sclerosis and stroke.

A new andrographolide-based terminal alkyne was synthesized in good yield from andrographolide by India's scientists. Andrographolide was obtained from a natural compound andrographolide , which in turn was isolated from the leaves of the plant .

Copper-catalyzed azide-alkyne cycloaddition reaction of alkyne with -sugars furnished a library of andrographolide-fastened triazolyl glycoconjugates in good yields. The structures of these semisynthetic andrographolide derivatives were established by Fourier transform infrared, NMR, and mass spectroscopy. The compounds were further evaluated against Alzheimer's disease using a scopolamine-induced memory impairment mice model. It was observed that antioxidant and anticholinesterase properties of these compounds contribute significantly toward their remarkable potential to improve cognitive functioning.

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Trihexyphenidyl (marketed as Artane and others) is an antispasmodic drug used to treat stiffness, tremors, spasms, and poor muscle control. It is an agent of the antimuscarinic class and is often used in management of Parkinson's disease. It was approved by the FDA for the treatment of Parkinson's in the US in 2003.

Artane has been shown to have several sides effects, some similar to Parkinson's symptoms, in particular people who are older or who have psychiatric conditions may become confused or develop delirium.

Despite growing concerns about Trihexyphenidyl causing cognitive decline in tremor-dominant Parkinson disease patients, the underlying neural correlates remain unclear. Therefore, the authors investigated the effects of this drug on prefrontal executive function and spontaneous neural activity in patients with tremor-dominant Parkinson disease by utilizing functional near-infrared spectroscopy.

The authors recruited 30 patients with tremor-dominant Parkinson disease, including 15 patients receiving the treatment and 15 patients not receiving Trihexyphenidyl.

The researchers performed comprehensive neuropsychological and clinical assessments to evaluate each patient's cognitive function, mental status, and clinical symptoms.

They measured brain activation elicited from the verbal fluency task and changes in amplitude of low-frequency fluctuations at rest to investigate executive function and spontaneous neural activity, respectively. In addition, the authors examined the relationship between altered activation during task and resting state and neuropsychological and clinical data.

Compared with tremor-dominant Parkinson disease patients not taking Trihexyphenidyl, tremor-dominant Parkinson disease patients taking the treatment showed no differences on neuropsychological tests.

However, there was insufficient activity of the dorsolateral prefrontal cortex, ventrolateral prefrontal cortex, and the orbitofrontal cortex related to the frontoparietal network at rest.

Furthermore, functional near-infrared spectroscopy results were positively correlated with scores of multiple cognitive domain functions.

These findings suggest that Trihexyphenidyl treatment may lead to prefrontal dysfunction in tremor-dominant Parkinson disease patients, attenuating brain activation in executive function and cognition-related spontaneous neural activity.

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