Integrated Stress Response (ISR) in neurodegenerative diseases

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There has been a recent surge in articles about the Integrated Stress Response (ISR) in neurodegenerative diseases. The hypothesis suggests that the ISR, a cellular mechanism for managing stress, becomes excessively prolonged in these conditions. Several refinements of this idea have been proposed, such as the notion that protein misfolding occurs because the endoplasmic reticulum cannot properly process proteins during ISR, leading to the accumulation of misfolded proteins in the cytoplasm, which causes various problems. For example, TDP-43 proteins fail to fold correctly and cannot be transported to the nucleus, where they play critical roles in DNA repair and virus defense.

In this blog, we have discussed this topic multiple times, including the Inflectis Sephin1/IFB-088 drug.

One such article about ISR is ALSUntangled #80, which discusses a drug called ISRIB (Integrated Stress Response Inhibitor).

Several ISR inhibitors have been identified, including Guanabenz, IFB-088, Salubrinal, and ISRIB. Some of these drugs, like Guanabenz, have significant side effects, making them less suitable for long-term and widespread use.

The outcomes of ALSUntangled are usually predictable; they tend to indicate that any drug they evaluate has limited interest for ALS. However, this time, it feels different, possibly because the two main authors, Javier Mascias Cadavid and Anna Mena Bravo, are from Spain.

They discuss ISRIB and how it was informally tested by 42 ALS patients in Spain, who reported subjective improvements and no side effects.

There are additional publications exploring whether ISRIB could be a promising treatment for ALS.

They say that ISR might be the culprit in a rare subtype of ALS, which is caused by a mutation in VAPB gene. The authors suggest that ISRIB might be useful. enter image description here What should we consider about all this? Maybe we should ask why scientists are searching for new drugs instead of focusing on compounds of drugs that have already shown some effects. Perhaps everyone wants to get rich, so they avoid exploring drugs that can't be patented.

For example, nobody has research on the benefits of Meclofenoxate in ALS in the last 50 years! A recent publication suggests it might be useful in Parkinson's disease.

Dynamic cycling and Parkinson's disease

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Can Exercise Mimic Dopamine Effects on Brain Signals in Parkinson’s Disease?

Parkinson’s disease (PD) is a progressive neurological disorder that affects movement and is partly caused by the loss of dopamine-producing neurons deep in the brain. While medications that replenish dopamine can help control symptoms, researchers are increasingly asking: Can other interventions, like physical exercise, offer similar benefits?

A recent study investigated this by examining how regular, vigorous cycling influences brain activity in people with Parkinson’s. The findings don’t suggest that exercise replaces medication, but they do reveal something intriguing: exercise may partially imitate how dopamine alters the brain’s internal rhythms.

What kind of exercise was used in the study? The study focused on a specific type called dynamic cycling. It’s not just casual biking; it involves riding a motor-assisted stationary bicycle at a steady, fast pace, usually between 75 and 90 pedal rotations per minute. This style of cycling has been linked to improvements in motor symptoms like stiffness and slowness in people with Parkinson’s. But this study wasn’t about clinical symptoms; it was about electrical signals inside the brain and what they reveal. enter image description here What did the researchers do? Nine individuals with Parkinson’s, all of whom had deep brain stimulation (DBS) implants, participated in up to 12 cycling sessions over a month. These implants allowed researchers to directly record brain activity from a small structure deep in the brain called the subthalamic nucleus (STN)—a region strongly involved in movement control and a common target in Parkinson’s treatments.

Before and after each exercise session, the researchers measured electrical signals from the brain, called local field potentials (LFPs). They analyzed two types of signals: - Periodic activity: rhythmic brain waves like beta waves. - Aperiodic activity: the background “noise” of brain signals, analyzed through a measure called the 1/f exponent.

What is the relationship between the hindbrain and subthalamic nucleus? Parkinson’s primarily involves the degeneration of dopamine-producing neurons in a midbrain area called the substantia nigra pars compacta (SNc). These neurons produce dopamine, a neurotransmitter vital for controlling movement. They project to other brain regions, notably the striatum. Loss of dopamine in the striatum causes the main motor symptoms of PD: tremors, slowness, stiffness, and balance issues.

The striatum uses dopamine to regulate two pathways: - The direct pathway (which promotes movement) - The indirect pathway (which inhibits movement)

The subthalamic nucleus (STN) is part of the indirect pathway and sends excitatory signals to the globus pallidus internus, which inhibits the thalamus, which in turn controls activity in the motor cortex.

In Parkinson’s loss of dopamine leads to overactivity of the indirect pathway, increasing activity in the STN. This overstimulates the GPi, which then excessively inhibits the thalamus. As a result, the thalamus cannot properly activate the motor cortex, causing slowed and reduced movement.

What did the researchers find? After a month of exercising, consistent changes appeared in brain signals from the dorsolateral part of the STN: - Power of rhythmic activity increased, indicating stronger brain waves. - The 1/f exponent also increased, suggesting the background neural activity became more organized and less noisy.

Interestingly, similar increases in the 1/f exponent occur when people take dopamine-based medication. This suggests that repeated exercise might induce brain states similar to those achieved with drug therapy, at least in certain regions.

However, not all areas of the STN showed changes. The ventral part of the STN remained unaffected, highlighting that the effects were both region-specific and gradual.

What does this mean? This study doesn’t claim that exercise cures Parkinson’s, nor does it prove symptom improvement directly linked to the brain changes observed. Instead, it shows that repeated, structured exercise can produce measurable alterations in brain electrical activity—some resembling the effects of dopamine therapy.

In other words, exercise might help “tune” the brain’s motor circuits to support better movement control, even if the mechanisms differ from medication. By directly measuring brain activity, this study provides early evidence that exercise can influence key brain areas involved in Parkinson’s.

It’s a reminder that improvements in Parkinson’s may come not only from drugs and surgery but also from consistent, targeted physical activity that stimulates the brain in new ways.

There are two ways to counteract the effects of dying neurons, and in both cases, physical activity plays a role. The first involves neighboring neurons forming new synapses to replace those that are lost. The second involves stem cells creating new neurons, but this process is limited by several factors: some neurons have complex structures connecting multiple brain areas, and in older individuals, the supply of stem cells is significantly decreased.

A study in Norway about drug repurposing

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Although effective symptomatic therapies have been developed for Parkinson's disease (PD), treatments that modify the disease itself still do not exist.

Drug repurposing studies help identify potential disease-modifying treatments. One advantage of drug repurposing is that, since these drugs are already approved, their safety profiles are known. However, further industry investigation is unlikely because companies hesitate to invest in drugs whose intellectual property is owned by others. Generally, they might consider repurposing their own drugs, which extends patent life by claiming new uses. This can also lead to questionable combinations of approved drugs just to file a patent.

In an issue of Neurology, Tuominen et al. publish a nationwide observational cohort study in Norway aiming to identify new candidates for disease modification in Parkinson's disease. They analyzed Norwegian health registries from 2004 to 2020 to identify people with Parkinson's. The study included 14,289 individuals and found 23 drugs among a total of 219 drugs associated with a reduced eight-year mortality risk.

Nonetheless, this reduction remains minor, and there is no proof that these drugs caused improved survival. enter image description here The authors note that, although their findings are exploratory and cannot be directly applied clinically yet, the identified drugs could be considered for future clinical trials. Indeed, funding should be sought for these future trials, and since it is almost always private investors who finance clinical trials, they would require more information before making any commitments.

However, this study has notable strengths compared to similar studies. Tracking specific disease milestones is crucial for evaluating the effects of potential disease-modifying treatments.

For nearly all of the 23 drugs discussed by Tuominen et al., the adjusted eight-year mortality curves for Parkinson's patients and healthy controls diverged and showed different slopes, suggesting these compounds may have a disease-modifying effect. This pattern has not been observed in other trials testing potential disease-modifying drugs.

When interpreting Tuominen et al.'s results, it is important to remember that correlation does not necessarily imply causation. A drug associated with lower mortality does not automatically prove that it caused the reduction.

On the one hand, the decreased mortality might simply reflect that healthier Parkinson's patients are more likely to be prescribed these drugs. For example, patients using tadalafil (for erectile dysfunction) may have better overall health and longer survival.

On the other hand, for the more difficult cases, some physicians may have focused solely on treating essential symptoms rather than prescribing a large number of medications.

Additionally, the number of patients in the "treatment" group is often small; for instance, only 170 patients used Levothyroxine sodium.

Does human pegivirus trigger Parkinson's disease?

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These days, major news stories about neurodegenerative diseases are rare. One headline in the trade press claims: "Harmless Virus Could Trigger Parkinson's Disease."

Most cases of Parkinson's disease are idiopathic, meaning the cause is unknown. However, several genetic mutations can also lead to this neurodegenerative disease, with approximately 20 to 25 percent of cases having a genetic cause. One of these mutations is in the gene encoding LRRK2, which can result in enzyme levels two to three times higher than normal. These mutations are more common in North African, Arab, Berber, Chinese, and Japanese populations. enter image description here

There is some good news coming out on this topic, but I'll talk about another publication.

Every viral infection alters the genetic material of some (but not all) cells in our body. This is how a virus forces the host cell to rapidly produce thousands of copies of itself. In most cases, viruses are first abruptly eliminated by the innate immune system, killing the host cell. The adaptive immune system uses a more intelligent mechanism, producing specific antibodies that bind to the virus and often render it non-infectious. This process is called humoral immunity. The LRRK2 protein is highly expressed in immune system cells, particularly in response to bacterial pathogens like Salmonella.

The hypothesis that some neurodegenerative diseases are caused by viral infections is attractive because it could explain why these diseases appear with age and why they affect the nervous system, as many viruses tend to accumulate there with age.

In a new study, researchers analyzed brains provided by the Rush Alzheimer's Research Center (RADC) in Chicago, from 10 autopsied Parkinson's patients and 14 non-PD patients. They found traces of human pegylated virus (HPgV) in five Parkinson's brains, but none in healthy brains. Human pegylated virus is a virus related to hepatitis C. The virus has also been detected in the cerebrospinal fluid of Parkinson's disease patients, but not in the control group. However, the small sample size makes these results inconclusive.

Next, perhaps seeking stronger evidence, the researchers analyzed blood samples from 1,393 participants in the Parkinson's Progression Markers Initiative, a biological sample bank for Parkinson's disease research. Only about 1% of Parkinson's patients had HPgV in their blood, which is consistent with the infection rate in the general population.

Nevertheless, the scientists say that people infected with the virus exhibited different immune signals, particularly those with a mutation in the LRRK2 gene. They explained that since mutations in the LRRK2 gene are known to influence immune signaling, autophagy, and viral processing, these genotype-specific responses suggest that host genetics and viral interactions could influence immune responses to human pegivirus, promoting neuroinflammation and the development of Parkinson's disease.

At this point, I'm confused; they performed two experiments, one not significant and the other negative, but in the article, the scientists still suggest a possible link between Parkinson's disease and human pegivirus. However, the headline and abstract (which will likely be the only parts colleagues read) are much less definitive: they only suggest that human pegivirus alters the transcriptomic profiles of patients with Parkinson's disease.

This is a far cry from the headlines in the trade press: "Harmless virus might trigger Parkinson's disease."

A Rare Gene Mutation Offers Clues to Combating Alzheimer’s and Cancer

The human immune system is not only our first line of defense against infectious threats, but it also plays an essential role in regulating how our bodies respond to internal dangers like cancer and neurodegenerative diseases.

One of the immune system’s tools is a molecular pathway known as cGAS-STING. This pathway functions as a sensor, detecting misplaced DNA in cells — a common feature in viral infections, cancer transformations, and some brain disorders.

A rare genetic mutation, first observed in 2019 in a woman with a strong inherited risk for Alzheimer’s disease, may help us better understand and even treat conditions such as Alzheimer’s, cancer, and autoimmune disorders. This woman, who carried a high-risk PSEN1 mutation that usually causes early-onset Alzheimer’s, remained cognitively intact into her seventies. Postmortem analysis revealed extensive amyloid plaques in her brain (a hallmark of Alzheimer’s) but very low tau pathology, which is more closely linked to memory loss and cognitive decline.

Genetic testing showed she carried two copies of a rare variant of the APOE3 gene: R136S, also known as the Christchurch mutation. APOE is a gene long known to influence Alzheimer’s risk, with different variants (APOE2, APOE3, and APOE4) conferring varying levels of protection or susceptibility.

What roles does the cGAS-STING pathway play? Under normal conditions, our cells keep their DNA tightly stored in the nucleus. But sometimes, DNA ends up in the wrong place — floating in the cytoplasm, the main body of the cell. This can happen due to viral infection, cellular stress, or genetic damage. The immune system interprets this misplaced DNA as a danger signal.

cGAS acts as a sensor activated primarily in two pathological contexts: microbial invasion by DNA viruses, bacteria, or retroviruses that introduce exogenous DNA into the cytoplasm, and aberrant leakage of nuclear or mitochondrial self-DNA into the cytosol. When cGAS detects double-stranded DNA in the cytoplasm, it produces a signaling molecule called cGAMP. This molecule then binds to a protein called STING (stimulator of interferon genes), activating a cascade that results in the production of type I interferons and inflammatory cytokines. These signals alert the immune system to potential threats and mobilize a defensive response. Interestingly, TDP-43, which is involved in several degenerative diseases, also has roles in protecting against DNA damage and viruses such as HIV.

While this response is critical for fighting infections and catching early-stage tumors, it can also become problematic when overactive. Persistent or misdirected cGAS-STING activity has been linked to autoimmune diseases, chronic inflammation, and cellular aging (senescence).

New Insights from Mouse Models To explore how exactly the R136S mutation offers protection, researchers engineered mice with human APOE3 or APOE3-R136S genes and introduced a tauopathy-causing mutation (P301S) mimicking key features of Alzheimer’s and frontotemporal dementia.

The findings were compelling: Mice carrying the R136S mutation showed less tau buildup, fewer signs of synaptic and myelin loss, and better brain activity patterns (theta and gamma oscillations important for learning and memory).

At the molecular level, the R136S mutation suppressed the cGAS-STING pathway in microglia, the brain’s resident immune cells.

When researchers treated APOE3 mice (a model of Alzheimer's) with a cGAS inhibitor, these animals exhibited many of the same benefits seen in people who are R136S carriers, including protection from tau-induced synaptic damage and similar gene expression changes across multiple brain cell types.

cGAS-STING: From Immunity to Neurodegeneration This research highlights a key insight: overactivation of cGAS-STING in microglia plays a damaging role in tau-driven neurodegeneration. Misfolded tau proteins can cause inflammation and disrupt brain networks, and microglia that respond too strongly—especially by ramping up interferon signaling through cGAS-STING—may inadvertently worsen the damage.

By reducing this response, the R136S mutation appears to create a more balanced immune environment in the brain. Instead of amplifying harmful inflammation, microglia can more effectively process and break down tau. enter image description here

The discoveries related to R136S and the cGAS-STING pathway have broad implications:

  • Cancer Immunotherapy: The same pathway that detects misplaced DNA in Alzheimer’s also helps identify cancer cells. Modulating cGAS-STING could improve immune responses against tumors or reduce chronic inflammation that promotes their growth.
  • Autoimmune Disorders: Conditions like Aicardi–Goutières syndrome involve constant activation of the cGAS-STING pathway, leading the body to attack itself. Understanding how mutations like R136S impact this response may aid in developing treatments that dial down harmful immune activity without compromising protective responses.
  • Healthy Aging and Senescence: The cGAS-STING pathway is also involved in cellular aging and the development of the senescence-associated secretory phenotype (SASP). Inhibiting this pathway could delay age-related degeneration and lessen age-related inflammation.

Looking Forward: From Mutation to Medicine

As discussed above, reducing cGAS-STING activity carries risks, including the potential to increase cancer susceptibility in older adults. Additionally, effects may vary across different cell types, benefiting the brain while impairing other vital organs. There are multiple schools of thought about what causes Alzheimer's disease; some incriminate the tau protein, but a majority of researchers are working on mitigating amyloid plaques. Another consideration —though obvious but not often explicitly stated— is that this research provides a preventive tool against Alzheimer's disease. In its early stages, it may slow the disease's progression, but it cannot cure someone who experiences the full impact of the disease.

In conclusion, the cGAS-STING pathway is a crucial sensor of misplaced DNA and a regulator of immune responses. A rare mutation in APOE3 (R136S) has been shown to suppress this pathway in brain immune cells, protecting against tau-related damage in Alzheimer’s models. This discovery opens new avenues for treating neurodegenerative diseases, autoimmune disorders, and cancer through precise modulation of our immune system’s ancient alarm system.

Perineuronal net modulation in a Parkinson's disease mouse model

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A growing number of studies are exploring the role of perineuronal nets (PNNs) in Parkinson’s disease. PNNs are specialized structures in the brain’s extracellular matrix that limit synaptic plasticity, like a stabilizing "glue" between neurons. While this stabilization helps maintain brain function in adulthood, it also reduces the brain’s ability to rewire or adapt, which is important for learning and recovery after injury. enter image description here PNNs are especially important during brain development. They help close the "critical period" of heightened plasticity in childhood. Interestingly, while PNNs are degraded in adults, this plasticity can be partially restored. For example, PNN removal can promote recovery in stroke models

PNNs serve multiple functions: protecting neurons from oxidative stress and harmful molecules, regulating plasticity, and helping stabilize long-term memories. Abnormal changes in PNNs have been observed in aging and various neurological conditions, making them a promising target for therapeutic intervention.

In the cerebral cortex, PNNs are primarily found around inhibitory interneurons, particularly those that produce the protein parvalbumin. These interneurons help maintain a balance between excitatory and inhibitory signals in the brain. In Parkinson’s disease, where dopamine-producing neurons in the substantia nigra are lost, this balance is disrupted—suggesting that changes in PNNs may contribute to the disorder.

A recent study investigated the effects of temporarily reducing PNNs in the primary motor cortex (M1) of healthy adult mice using chondroitinase ABC (ChABC). This intervention caused temporary impairments in motor function, suggesting that PNNs contribute to motor stability. Using ChABC makes sense as perineuronal nets are composed of chondroitin sulfate proteoglycans, and ChABC is an enzyme that digests them. Chondroitinase treatment has been shown to allow adults' vision to be restored; moreover, there is some evidence that Chondroitinase could be used for the treatment of spinal injuries.

The researchers created a Parkinson’s disease mouse model by damaging one side of the midbrain of mice with 6-hydroxydopamine (6-OHDA). Two weeks after the lesion, PNN levels dropped in both hemispheres of the motor cortex but returned to normal within five weeks.

The researchers then applied ChABC to reduce PNNs again in the motor cortex and paired this with motor training. This combination improved motor recovery slightly in the Parkinsonian mice. The improvement was linked to an increase in parvalbumin interneurons surrounded by PNNs and a normalization of excitatory signals at their cell bodies. These findings suggest that PNNs respond dynamically—first to the injury and later to therapeutic intervention—and that manipulating them could help restore motor function.

In summary, perineuronal nets in the motor cortex appear to play a subtle but significant role in regulating movement. Modifying their structure could open new avenues for motor rehabilitation in Parkinson’s disease.

Parkinson's disease and acupuncture

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I am somewhat skeptical about the benefits of acupuncture beyond the placebo effect. However, this article suggests it could be beneficial for individuals with Parkinson's disease.
enter image description here This study investigates whether acupuncture has any impact on long-term health outcomes, such as mortality, disease progression, or complications, in individuals newly diagnosed with Parkinson’s disease (PD) in South Korea. Indeed, it is unclear what constitutes an effective acupuncture session for Parkinson's disease, and individuals interested should receive at least one session every two months. It is commonly believed that in PD, reduced mobility due to tremors, postural imbalance, and rigidity likely contributes to poor circulation and decreased gastrointestinal motility, leading to bowel obstructions and impaired swallowing, which can, in turn, result in recurrent aspiration pneumonia. The benefits may arise from the fact that people with PD might find it easier to move.

As is often the case, the Korean authors used a database to select patients and gather information about their health over the following years. They did not see any patients in person; it was purely a matter of processing numbers in the database. The NHIS database contains extensive patient information, including diagnostic codes, healthcare utilization, prescriptions, vital signs, disability grades, sex, age, and socioeconomic factors such as health insurance. However, this database does not provide precise medical details.

Who Was Included in the Study?

The study focused on adults (age 19 or older) newly diagnosed with idiopathic Parkinson’s disease (IPD) between 2012 and 2016.

To ensure a cleaner analysis, the authors excluded individuals diagnosed with Parkinson’s before 2012 or who were disabled at the time of diagnosis. They also excluded patients diagnosed with dementia or who died within a year of their diagnosis. To strengthen the results, they excluded patients who had received acupuncture in the six months preceding their diagnosis.

After applying these exclusions, about 41,000 patients remained. From this group, the researchers employed "propensity score matching" to pair patients from both groups who had similar health and demographic profiles (like age, sex, income, location, and other health conditions). After further exclusions and matching, 6,394 patients remained in each group.

The researchers measured all-cause mortality (death from any cause), tracked for up to six years following diagnosis. They also recorded fractures (such as hip or spine fractures), emergency room visits, and deep brain stimulation (DBS) surgery. These outcomes serve as proxies to assess whether acupuncture is associated with slower disease progression or fewer complications.

How Were Acupuncture and Non-Acupuncture Groups Defined?

Acupuncture was counted only if a person had six or more sessions in the year following diagnosis. This cutoff is based on previous studies suggesting that at least six sessions may be necessary to observe an effect. The acupuncture types included conventional methods as well as specialized forms like ocular or electroacupuncture.

Results:

Overall, the mortality in the acupuncture group (960) was significantly lower than in the control group (1,118). Deaths due to neoplasms (174 vs 234), circulatory (172 vs 208), and digestive diseases were also lower in the acupuncture group. In all cases, the acupuncture group had equal or better results than the control group. However, no significant differences were observed between groups in fracture risk, emergency room visits, or DBS procedures.

Key Takeaways

The study aimed to explore whether acupuncture might influence survival or disease progression in Parkinson’s disease. To achieve this, it utilized a large, high-quality national health dataset and careful matching to compare similar patients. While the text does not cover the results themselves (e.g., whether acupuncture improved survival or reduced complications), the methods ensure that any differences found are likely due to the treatment rather than other health or demographic factors.

Blood Lipoprotein Levels and Alzheimer Disease

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Recent research continues to highlight the complex relationship between cardiovascular health and brain aging. For instance, vascular dementia is one type of dementia. Furthermore, universities are encouraging their teams to identify useful biomarkers for neurodegenerative diseases, as they believe they can generate revenue from potential patents. One quick and inexpensive method to conduct a study is to utilize databases available online.

The Framingham Study is a long-term epidemiological study (since 1948) that initially focused on cardiovascular disease. We owe much of our knowledge about cardiovascular disease to the Framingham Study, particularly regarding the identification of cardiovascular risk factors, including the effects of smoking and diet. Thus, the recognition of high blood pressure as a risk factor for heart disease dates back to 1957, for neurological diseases to 1967, and heart failure to 1971. enter image description here By Manu5 - http://www.scientificanimations.com/wiki-images/

At the same time, the Framingham Study focused on a relatively affluent population of European origin, meaning the conclusions drawn from it may not necessarily apply to other populations. Furthermore, marker values vary depending on the data collection devices and methods (some values date back to 1948!), so an a priori analysis must consider these difficulties, which is rarely addressed in rapid studies.

The authors of the article discussed in this post selected 822 elderly individuals (mean age: approximately 72 years) from the database who were not suffering from dementia at the time of their first blood test with the Framingham Study. Participants were monitored for Alzheimer's disease until 2020. Over a median follow-up period of 12.5 years, 128 of these individuals developed Alzheimer's disease.

The article authors measured levels of high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), small dense LDL cholesterol (sdLDL-C), lipoprotein a (Lp(a)), apolipoprotein B (ApoB), and the ApoB48 isoform of ApoB in the blood samples collected from 1985 to 1988 by the Framingham Study.

It has long been acknowledged that, although the mechanism is not fully understood, elevated levels of apolipoprotein B (ApoB) are associated with higher concentrations of LDL particles and are the primary driver of plaques that cause vascular disease (atherosclerosis), which typically first manifests as obvious symptoms such as heart disease, stroke, and various other body-wide complications after decades of progression.

Furthermore, the causes of Alzheimer's disease remain poorly understood, but the most significant genetic risk factor arises from an allele of apolipoprotein E. Other risk factors include a history of head trauma, clinical depression, and high blood pressure. The progression of the disease is largely characterized by the accumulation of malformed protein deposits in the cerebral cortex, known as amyloid plaques and neurofibrillary tangles.

Therefore, there is a possible link between dementia and cardiovascular risk, and the Framingham Study database allows us to statistically compare heart health and the risk of developing comorbidities.

The article authors considered a wide range of cholesterol-related markers:

  • HDL-C: "Good" cholesterol

  • LDL-C: "Bad" cholesterol

  • sdLDL-C: Small, dense particles of LDL cholesterol

  • ApoB and ApoB48: Proteins involved in cholesterol transport

  • Lp(a): A lipoprotein linked to the risk of heart disease

The researchers examined the relationship between these markers, standardized by their standard deviation units (SDUs), and the future risk of Alzheimer's disease.

** sdLDL-C ** They found that high sdLDL-C levels correlate with an increased risk of developing Alzheimer's disease. This result has also been observed by other teams, including a recent one that examined a database in Finland:

SdLDL-C stands for "small dense low-density lipoprotein cholesterol." It is a subclass of LDL particles that are smaller and denser than conventional LDL and more likely to penetrate blood vessel walls. This cholesterol subtype is rarely tested. sdLDL is regarded as a more atherogenic lipoprotein due to its higher retention rate in the arterial wall, better penetration, lower binding affinity to the LDL receptor, lower resistance to oxidative stress, and longer plasma half-life. In addition to being associated with a heightened risk of cardiovascular disease, sdLDL, particularly sdLDL-C levels, have been linked to type 2 diabetes mellitus, metabolic syndrome, obesity, and low-grade inflammation.

** ApoB48 ** Conversely, elevated ApoB48 levels are linked to a reduced risk of Alzheimer's disease. This finding was previously known.

** HDL-C ** However, the authors uncovered surprising results regarding HDL-C, often referred to as "good cholesterol". Numerous epidemiological studies have indicated that high circulating HDL levels are associated with a reduced risk of Alzheimer's disease. Yet, this new study's authors found that participants with the lowest HDL-C levels had a 44% reduced risk of developing Alzheimer's disease compared to those with higher HDL-C levels.

Because HDL-C is generally considered protective, this team's findings may reflect other age-related changes, such as metabolic status or weight loss, that occur before the onset of dementia.

Jacifusen pour FUS-ALS : une étude de cas

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Les oligonucléotides antisens (ASO) sont de petites séquences d'ADN capables de réduire l'expression d'un gène cible au niveau post-transcriptionnel, ce qui les rend intéressants pour neutraliser les produits génétiques mutants ou toxiques. enter image description here Les progrès réalisés dans la chimie médicinale des ASO ont amélioré leur profil pharmacodynamique, permettant ainsi une administration sûre et efficace au système nerveux central. Les thérapies ASO pour la SLA se sont rapidement développées au cours des deux dernières décennies, et les ASO ciblant SOD1, C9orf72 et ATXN2 sont actuellement en essais cliniques pour les formes familiales ou sporadiques de SLA.

L'injection directe dans le SNC permet à l'ASO de se distribuer dans tout le SNC, et les ASO ciblant SOD1 (Tofersen/Qalsody) ont démontré que l'administration intrathécale était une approche bien tolérée. De nouvelles approches d'administration, telles que la conjugaison des ASO à des nanoparticules lipidiques ou à des cholestérols, pourraient bientôt permettre une administration moins intrusive et pouvant être effectuée par davantage de professionels.

Les mutations du sarcome fusionné (FUS) sont à l'origine d'une forme rare et agressive de SLA, d'apparition précoce et souvent juvénile. FUS est une protéine de liaison à l'ARN essentielle à la réparation et au métabolisme de l'ADN, notamment à l'épissage et à la traduction de l'ARNm.

Alors que la plupart des formes de SLA présentent généralement une pathologie TDP-43, les tissus post-mortem de patients atteints de SLA présentent une agrégation intracytoplasmique en l'absence de pathologie TDP-43. enter image description here Identifié par criblage in vitro, l'ASO ION363 développé par la société IONIS qui a aussi développé Tofersen, cible le 6e intron de FUS (SLA avec une mutation P525L). ION363 réduit les taux de protéines de liaison à l'ARN insolubles et insolubles associées aux agrégats, telles que hnRNPA1 et ralentit la neurodégénérescence des motoneurones lombaires et la perte d'innervation de la jonction neuromusculaire.

L'inversion de la neurodégénérescence et la réduction de la prolifération chez les souris P525L ont motivé une demande d'IND (« usage compassionnel ») pour des tests chez l'homme porteur de mutations. Une demande d’IND a été approuvée par la FDA pour l’utilisation d’ION363 chez un patient atteint de SLA porteur d’une mutation P525L (âgé de 26 ans).

Jaci Hermstad, une jeune femme de 25 ans originaire de l'Iowa, a reçu un diagnostic de SLA-FUS, huit ans après avoir perdu sa sœur jumelle, atteinte de la même maladie, à l'âge de 17 ans. La famille Hermstad a contacté Project ALS et le Dr Shneider, qui étudiait le potentiel des ASO dans le traitement des patients atteints de SLA-FUS, pour savoir s'il existait des thérapies susceptibles d'aider Jaci.

« L'histoire des Hermstad a immédiatement attiré l'attention de nombreuses personnes talentueuses et bienveillantes, d'Ionis et du Dr Shneider, expert du gène FUS, aux experts réglementaires bénévoles, aux fabricants et aux conseillers universitaires », a déclaré Valerie Estess, directrice de recherche du Project ALS. Le courage de Jaci, et le travail d'équipe qu'elle a inspiré, peuvent désormais porter leurs fruits pour tous les patients atteints de SLA-FUS.

Grâce au financement de l'ALS Association et du Projet SLA, le Dr Shneider et son équipe de Columbia ont pu proposer le jacifusen à dix patients supplémentaires atteints de SLA-FUS au cours des deux dernières années, tout en suivant en parallèle les données de sécurité du médicament et les biomarqueurs pertinents pour la maladie.

Cela a conduit la Chambre des représentants des États-Unis à adopter le projet de loi de Jaci, autorisant les médecins à administrer l'ASO avant de réaliser des tests toxicologiques sur des rongeurs. Selon sa nécrologie, Hermstad a reçu 12 injections du médicament, appelé Jacifusen, entre juin 2019 et mars 2020 avant de décéder de la SLA le 1er mai 2020.

À l'autopsie, l'ION363 a été largement détecté dans les tissus du cerveau et de la moelle épinière, deux mois après la dernière perfusion. Les signes pathologiques de la SLA-FUS P525L ont diminué, notamment les inclusions cytoplasmiques neuronales positives, les agrégats insolubles de protéines de liaison à l'ARN et d'autres protéines, ainsi que la localisation nucléaire.

Un examen neuropathologique a été réalisé chez le premier participant, ainsi que chez un témoin non atteint de SLA et un patient atteint de SLA porteur de la mutation P525L n'ayant pas reçu de traitement. Par rapport au témoin atteint de SLA, le participant traité par ASO présentait moins de protéines totales et mutantes, y compris de protéines insolubles, dans la moelle épinière lombaire.

Shneider et son équipe à Columbia ont proposé du Jacifusen à dix patients supplémentaires atteints de SLA au cours des deux dernières années.

En juin 2021, Ionis a lancé un essai de phase 3 appelé ION, visant à traiter jusqu'à 77 patients dans le monde. Les participants sont âgés de 11 ans et plus, atteints de SLA causée par une mutation pathogène confirmée du gène ION363 et ne doivent pas être sous ventilation mécanique permanente au moment de l'inscription. Ils reçoivent des injections rachidiennes d'ION363 ou d'un placebo toutes les douze semaines, après une dose de charge à quatre semaines, pendant 61 semaines, suivies d'une prolongation en ouvert de 85 semaines. Le critère d'évaluation principal est l'évolution fonctionnelle selon l'échelle d'évaluation fonctionnelle de la SLA révisée et la durée de vie sans ventilation mécanique. Les critères d'évaluation secondaires incluent la qualité de vie, la fonction pulmonaire et musculaire, la survie et les modifications du biomarqueur des chaînes légères des neurofilaments. Réalisé à L'essai clinique, mené sur 24 sites en Amérique du Nord, en Europe, au Royaume-Uni, à Taïwan et en Corée, devrait se poursuivre jusqu'en juin 2026.

La deuxième partie de l'étude consiste en une période d'extension ouverte de 72 semaines au cours de laquelle tous les participants ont reçu du jacifusen.

Une caractéristique unique de cet essai est la mise en œuvre d'un « sauvetage ». Plus précisément, si un participant présente un déclin fonctionnel significatif au cours de la première partie, il sera transféré vers la deuxième partie/extension ouverte de l'étude. Cela semble suspect du point de vue statistique: L'étude ne conserve que les patients qui évoluent lentement!

Bien que la plupart des participants aient connu un déclin fonctionnel continu (mesuré par l’ALSFRS-R) après le début du traitement par jacifusen, l’un d’eux a présenté une récupération fonctionnelle objective sans précédent après 10 mois, et un autre est resté asymptomatique, avec une amélioration documentée des anomalies électromyographiques.

How to cope with the deluge of scientific publication?

- Posted by admin in English

At Padiracinnovation, we face a paradox: despite the deluge of scientific publications on ALS, Parkinson's, and Alzheimer's disease, academic and industry scientists seem unable to develop effective drugs.

In fact, the incentive for academic scientists appears to be publishing a large volume of work, as this is nearly their only path to career advancement. Industry scientists publish infrequently, but their work primarily serves to promote their company to potential investors.

How can we differentiate the wheat from the chaff? There are several telltale signs:

  • single author

  • authors who publish more than two papers per year

  • publishing outside of prominent journals, such as in conferences

  • articles based on specific intuition without testing other hypotheses

  • articles concerning a specific drug without explaining the rationale for its initial selection

  • articles making bold claims based on queries to a public database without conducting further research to validate the results and without considering confounding factors

  • articles making outrageous claims, such as "breakthrough in disease X."

In our field, additional indicators exist: a strong publication should report results from human trials, as animal models often prove to be completely ineffective.

Consequently, we find few publications to discuss, even as popular science news organisations report daily on significant advances made toward new drugs.


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