Articles written in English

Hepatitis E virus may be associated with neurodegenerative disorders in the elderly

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Neurodegenerative diseases are often sometimes to a virus, in particular HERV-K, but this has never been demonstrated convincingly.

Hepatitis E virus (HEV) infections are not limited to the liver but can also affect other organs. Several neurodegenerative diseases including Guillain-Barré syndrome, neuralgic amyotrophy, meningitis, have been observed in the context of hepatitis E. Additionally, HEV infection has been observed with other neurological diseases, such as encephalitis, myelitis, and Bell's palsy. Patients may have normal liver function tests, which can often mislead doctors into inferring that there is no HEV infection. enter image description here

Case-control studies are a type of epidemiological study. They have often been used in the study of rare diseases where little is known about the association between the risk factor and the disease of interest.

Case-control studies are used to identify factors that may contribute to a disease by comparing subjects who have that disease (the “cases”) with patients who do not have the disease but are otherwise similar (the “controls”).

In this case-control study, scientists from Spain assessed the association between serum antibodies against the hepatitis E virus and neurodegenerative disorders of the central nervous system in older people with dementia.

The presence of anti-HEV antibodies was related to a higher adjusted odds ratio of having neurodegenerative disorders by neuropathological diagnosis and clinical/neuropathological diagnosis.

Furthermore, serum anti-HEV antibodies were directly linked to neuropathological injury and a higher likelihood of having Alzheimer-like pathology.

The scientists conclude their article by assuming that the presence of anti-HEV antibodies was indeed linked to a higher risk of neurodegenerative disorders and neuropathological lesions in the elderly.

However, the reader should exercise caution. Case-control studies are observational in nature and do not provide the same level of information as randomized controlled trials. The results can be distorted by other factors, sometimes significantly.

Genetic and epigenetic signatures associated with plasma oxytocin levels in children and adolescents with autism spectrum disorder

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This is another study about oxytocin role in autism. It reflects a view of autism as mainly about communication skills. Yet autism's diagnostic is not standardized, and as for some other diseases biomarkers are actively seeked as hopes for a genetic origin have been dashed.

Oxytocin (OT), the brain's most abundant neuropeptide, plays an important role in social salience and motivation. Studies have looked at oxytocin's role in various behaviors, including orgasm, social recognition, pair bonding, anxiety, in-group bias, autism, and maternal behaviors.

As Oxytocin is believed to have a significant role in social learning, it has been implicated in the etiology of autism, with one report suggesting autism is correlated to a mutation on the oxytocin receptor gene (OXTR). Low levels of oxytocin could become a new biomarker for individuals that fall into the Autism Spectrum.

Yet clinical trials of the efficacy of oxytocin in autism spectrum disorder (ASD) have reported mixed results due in part to autism spectrum disorder complex etiology. The scientists here hypothesized that genetic and epigenetic variation contribute to variable endogenous oxytocin levels that modulate sensitivity to oxytocin therapy.

To test this hypothesis, the authors integrated genome-wide profiles of DNA-methylation, transcriptional activity, and genetic variation with plasma oxytocin levels in 290 participants with autism spectrum disorder enrolled in a randomized controlled trial of oxytocin.

Their analysis shows subtle, but statistically significant association of plasma oxytocin levels with peripheral transcriptional activity and DNA-methylation profiles across several annotated gene sets. The scientists also identified genetic variants with novel association with plasma oxytocin, several of which reside in known autism spectrum disorder risk genes.

These findings broaden authors' understanding of the effects of the peripheral oxytocin system and provide novel genetic candidates for future studies to decode the complex etiology of autism spectrum disorder and its interaction with oxytocin signaling and oxytocin-based interventions.

Read the original article on medRxiv

Biogen stops working on BIIB100, one of its three amyotrophic lateral sclerosis (ALS) drug candidates

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Biogen is discontinuing BIIB100 (an XPO1 inhibitor) as one of its three amyotrophic lateral sclerosis (ALS) drug candidates. This is a sad news as Tofersen, an ASO, its most advanced of the three ALS programs, failed recently to hit the primary endpoint, even as Biogen has made the case for the asset and engaged with regulators about the next steps.

Biogen’s other clinical-phase ALS candidate is BIIB105, another antisense asset. BIIB105 is in a phase 1 clinical trial designed to assess its effect on two forms of ALS.

Biogen partnered on BIIB100 in 2018 with a biotech named Karyopharm Therapeutics which wanted to focus on their cancer pipeline. The idea was that if BIIB100 was successful, then Biogen would bought it for $207 million.

Biogen began a Phase 1 trial in 49 adults with ALS the following year to investigate whether reducing nucleoprotein export by inhibiting the nuclear transport factor XPO1 can prevent the formation of neuronal cytoplasmic inclusions and thus slow the sporadic progression of ALS.

Work on the study was completed in June 2021. On June 7, 2022, Biogen wrote to Karyopharm terminating the agreement, with Karyopharm notifying investors eight days later.

BIIB100 crosses the blood-brain barrier more readily than other selective inhibitors of nuclear export compounds. It's also supported by research suggesting it causes the binding and blocking of NF-κB, a protein involved in inflammation.

It's not clear to me why Biogen saw a great potential for a XPO1 inhibitor in ALS. XPO1 exports several hundreds of different proteins from the nucleus. XPO1 is involved in various viral infections and in many cancer.

Contact the author


This book retraces the main achievements of ALS research over the last 30 years, presents the drugs under clinical trial, as well as ongoing research on future treatments likely to be able stop the disease in a few years and to provide a complete cure in a decade or two.

Flavonoid and chromone-rich extract from Euscaphis Konishii Hayata leaf attenuated alcoholic liver injury in mice.

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Contrary to appearances, there is some links in this post with neurodegenerative diseases. Alcoholic liver injury are one kind of cellular stress. All drugs that can treat cellular stress, and especially Endoplasmic Reticulum (ER) stress, can probably be used against most common neurodegenerative diseases. The same is true for drugs with free radicals scavenging activity.

Euscaphis konishii Hayata is a traditional medicinal plant in China, and its leaves are usually used to make dishes for hepatic or gastrointestinal issues by Chinese She nationality. Hepatocellular carcinoma (hepatoma) is the most common type of primary liver cancer in adults. Hepatocellular carcinoma causes 662,000 deaths worldwide per year about half of them in China.

Pharmacological analysis showed that E. konishii leaves contain high levels of flavonoids and chromones with favorable anti-hepatoma effect. 8 flavonoids and 2 chromones were recognized in the chromone-rich extract. Chromones are found throughout the plant kingdom, where they serve as essential components of a number of structural polymers, provide protection from ultraviolet light, defend against herbivores and pathogens, and also mediate plant-pollinator interactions as floral pigments and scent compounds.

Alcohol-fed mice disease model were used to assess the hepatoprotective effects of these chromone-rich extract.

Chromone-rich extract represented strong free radicals scavenging activity in vitro. With oral administration, chromone-rich extract dose-dependently decreased the serum levels of alanine aminotransferase, alkaline phosphatase and aspartate aminotransferase in alcohol-fed mice.

Chromone-rich extract gradually increased the activity of superoxide dismutase and glutathione peroxidase in the alcohol-treated liver tissues. Chromone-rich extract also alleviated the hepatic inflammation, inhibited the hepatocyte apoptosis and lessened the alcohol-induced histological alteration and lipid accumulation in the liver tissues.

Chromone-rich extract administration inhibited the overexpression of endoplasmic reticulum chaperones signaling and unfolded protein response pathways to defense the ER-induced apoptosis. Pretreatment with chromone-rich extract also restored the mitochondrial membrane potentials andadenosine triphosphate levels, which in turn suppressed the Cytochrome C release and mitochondria-induced apoptosis.

Chromone-rich extract conferred great protection against alcoholic liver injury, which might be associated with its viability through suppressing reactive oxygen species stress and hepatocyte apoptosis.

It may be possible they also have positive effects in neurodegenerative diseases.

Read the original article on Pubmed

Quality of life was better with CNM-Au8 than with placebo nearly one year after the start of the ALS treatment.

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The RESCUE-ALS trial (NCT04098406) enrolled 45 people with early-onset ALS, who were assigned randomly to take CNM-Au8 (30 mg/day) or a placebo for 36 weeks (about nine months). Participants then had the option to enter an open-label extension study in which all were given CNM-Au8. Results were presented in November 2021.

It's a phase II trial, which means it was designed to assess how well the drug works, as well as to continue Phase I safety assessments in a larger group of volunteers and patients.

The trial, did not meet its primary and a key secondary goal after 36 weeks of treatment: higher Motor Unit Number Index (MUNIX) scores — which measure the number, function, and health of motor neurons — and greater forced vital capacity (FVC), a measure of lung health. However, a trend toward better MUNIX scores was evident at 12 weeks among patients taking CNM-Au8.

In addition, quality of life at week 36 was significantly better in patients taking the investigational therapy, and there was evidence of benefit in long-term survival.

Over the eight-month trial, the therapy was also found to be relatively well-tolerated with no reported life threatening adverse events related to treatment.

It was followed by an open label trial. The data has accumulated and some new results of this open label trial were presented at ENCALS (2022 European Network to Cure ALS).

One poster (a low cost way to present results in scientific conferences) suggests that survival was improved by 24 weeks. Yet the phrasing is not very clear, it tells that early and continuous treatment with CNM-Au8 reduced mortality risk by 62% compared to delaying treatment. In one case one knows they can live longer, in the other case one can expect to be in the lucky people who would not die early.

A second poster is less bold, but clearly shows that quality of life was better with CNM-Au8 tha with placebo nearly one year after the start of the treatment. A third one reiterates that quality of life was better with CNM-Au8.

An ongoing platform clinical trial called HEALEY (NCT04297683) is testing the effectiveness of CNM-Au8 alongside several other potential ALS therapies. Results are expected later this year.

While all those good results are welcomed, one should reminds itself that in the world of biotechs it is common practice to make excessive announcements in order to attract investors. Here what could refrain enthusiasm is the lack of scientific publications on CNM-Au8, except those posters. Posters are usually presented by students, not by professional scientists.

Clene Nanomedicine claims that CNM-Au8 is a catalytic gold nanoparticule, which probably means it accelerates metabolic reactions. Usually nanoparticles are used to vehicle a drug, for example mRNA in COVID vaccines. So far CNM-Au8 has been demonstrated to be an efficient catalyst for metabolic energy reactions, converting the energetic metabolite nicotinamide adenine dinucleotide hydride (NADH) into NAD+ in proof-of-principle cell-free assays.

It's not clear what makes CNM-Au8 so successful in ALS. There is no publications on animal models of ALS. One can wonder why there is no more regulatory supervision on the organization of new clinical trials.

Let's hope these good results it will trigger more and more opened research in the area of nanoparticles for ALS.

Differentiating Slowly Progressive Subtype of Lower Limb Onset ALS From Typical ALS Depends on the Time of Disease Progression and Phenotype.

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What's in a name? Is Flail leg syndrome a variant of ALS or another disease? There are many anomalies in medicine, for example cancer sufferers in Western Europe could have a much different life expectancy when moving abroad, even when the new country is very similar to the country of origin.

It's a bit similar in ALS, it looks like ALS is not exactly the same disease in US, EU or Asia. Sometimes there is a understandable reason for example the statistical frequency of SOD1 mutations is different in Asia from US. Sometimes it is simply a matter of different semantics, some neurologists tell ALS is both upper and lower motor neurons, others have different opinions.

"Flail leg syndrome" is a Asian variant of amyotrophic lateral sclerosis with the characteristics of slow progression and the symptoms confined to the lumbosacral region for extended periods. In US it would have probably been called "Progressive Muscular Atrophy".

Yet there is no genetic background behind Flail leg syndrome, so why is it a regional appellation? In this new publication the scientists astonishingly decided that a slow progressing disease must be called "Flail leg syndrome".

The objective of a new study was to determine a cutoff time of disease progression that could differentiate Flail leg syndrome from the typical lower limb onset Amyotrophic Lateral Sclerosis.

A cutoff point analysis was performed with maximally selected log-rank statistics in patients with lower limb onset Amyotrophic Lateral Sclerosis registered from 2009 to 2013.

Based on the cutoff duration from the lower limb onset to second region (14 months), all patients were divided into the slowly progressive subtype of lower limb onset Amyotrophic Lateral Sclerosis group and the typical lower limb-onset Amyotrophic Lateral Sclerosis group.

Unsurprisingly the FLS was characterized by slower progression, less and later respiratory dysfunction, and a more benign prognosis than the typical lower limb onset Amyotrophic Lateral Sclerosis.

Patients with FLS exhibited a median diagnostic delay of 25 months, a median duration of 24 months from lower limb onset to second region, a forced vital capacity abnormity rate of 12.5% at the first visit to authors' department, and a median survival time of 80 months, which were significantly different from those of patients with typical lower limb onset Amyotrophic Lateral Sclerosis. The 5-year survival rate of the FLS group was much higher than that of the other group.

Now what all this mean? That if you select patients with a slow progression, you find they have a slow progression, is it high quality science?

Read the original article on Pubmed

Annual Trends in the Incidence and Prevalence of Alzheimer's Disease in South Korea: A Nationwide Cohort Study.

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Despite recent studies suggesting a declining incidence and prevalence of dementia on a global scale, epidemiologic results with respect to Alzheimer's disease are lacking due to the methodological limitations inherent to conducting large-scale cohort investigations of this topic.

The aim of the current study was to investigate the incidence and prevalence of Alzheimer's disease in Korea.
The authors conducted a secondary analysis within the National Health Insurance System database, a unique resource that reports medical information for the entire Korean population.

Alzheimer's disease diagnoses as well as evaluations of vascular risks were defined based on International Statistical Classification of Diseases codes along with prescription records.

In this study, the incidence and prevalence of Alzheimer's disease in the Korean population aged 40 years or older showed an overall increase between 2006 and 2015.

Although both older and younger age groups showed an increase in the incidence and prevalence of Alzheimer's disease, the highest increase was observed in older age groups. Which is the inverse of the previous reports.

The average value for the diagnosis of Alzheimer's disease was found to be 69 years.

The incidence of Alzheimer's disease was higher in individuals with underlying vascular risks. However, in recent years, the prevalence of Alzheimer's disease was conversely found to be lower in individuals with hypertension or dyslipidemia.

Read the original article on Pubmed

Alterations in somatosensory, visual and auditory pathways in amyotrophic lateral sclerosis: an under-recognised facet of ALS.

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While amyotrophic lateral sclerosis is widely recognised as a multi-network disorder with extensive frontotemporal and cerebellar involvement, sensory dysfunction is most of the time denied as "ALS is a motor neuron disease", despite the wide reports of pain by patients and multiple MRI studies telling degeneration in many areas in the brain. This study complements the work in this area, hopefully many progress could be expected when scientists will stop to think of ALS as only "a motor neuron disease".

In a prospective neuroimaging study the authors have systematically evaluated cerebral grey and white matter structures involved in the processing, relaying and mediation of sensory information. Twenty two C9orf72 positive Amyotrophic Lateral Sclerosis patients, 138 C9orf72 negative Amyotrophic Lateral Sclerosis patients and 127 healthy controls were included.

Widespread cortical alterations were observed in C9+ Amyotrophic Lateral Sclerosis including both primary and secondary somatosensory regions. In C9- Amyotrophic Lateral Sclerosis, cortical thickness reductions were observed in the postcentral gyrus.

Thalamic nuclei relaying somatosensory information as well as the medial and lateral geniculate nuclei exhibited volume reductions. Diffusivity indices revealed posterior thalamic radiation pathology and a trend of left medial lemniscus degeneration was also observed in C9- Amyotrophic Lateral Sclerosis.

The authors' radiology data confirm the degeneration of somatosensory, visual and auditory pathways in Amyotrophic Lateral Sclerosis, which is more marked in GGGGCC hexanucleotide repeat expansion carriers.

In contrast to the overwhelming focus on motor system degeneration and frontotemporal dysfunction in recent research studies, authors' findings confirm that sensory circuits are also affected in Amyotrophic Lateral Sclerosis.

The involvement of somatosensory, auditory and visual pathways in Amyotrophic Lateral Sclerosis may have important clinical ramifications which are easily overlooked in the context of unremitting motor decline.

Read the original article on Pubmed

Can cell and gene therapies improve cognitive symptoms in Parkinson's disease?

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Advanced therapies, including cell and gene therapies, are in development for Parkinson's disease. In many cases, the goal is to replace the lost dopamine, which is anticipated to improve motor dysfunctions associated with dopamine loss. This publication casts some doubts on this strategy.

For Mariah J Lelos from Cardiff University, it is not clear the extent to which these therapeutic interventions may impact on the wide range of cognitive symptoms that manifest as the disease progresses.

Although the accepted perception is that cognitive symptoms are predominately non-dopaminergic in origin, in this commentary, Lelos argues that several, specific cognitive processes, such as habit formation, working memory and reward processing, have been reported to be dopamine-dependent.

Furthermore, there is evidence of dopaminergic medications modulating these behaviors in Parkinson disease patients. Finally, the potential for cell and gene advanced therapies to influence these symptoms is considered.

Lelos concludes that dopamine replacement through advanced therapies is likely to improve certain dopamine-dependent symptoms, but only sparse clinical data are currently available and the ability to precisely titrate dopamine transmission is likely to be complex.

Read the original article on Pubmed

Proteins alterations observed in neurodegenerative disorders could be linked to the minimization of proteomic costs

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Aging is an important risk factor for neurodegenerative disorders (neurodegenerative disorders), including Alzheimer's disease (AD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS) and Huntington's disease (HD ).

Protein synthesis has historically been described as decreasing with age, although not all studies agree and often point to high organ and tissue variability. Protein degradation is also commonly described as compromised in aging

Analysis of brain protein levels in the physiologically aged brain, however, showed only minor changes in protein abundance in the older adult brain compared to the young adult brain. However, a recent theory indicates that the alterations observed in neurodegenerative disorders could be linked to the minimization of proteomic costs, reflecting a new prioritization of bioenergetic costs, which would preserve the most "expensive" proteins in energy from the aged brain while replacing more easily metabolically less expensive proteins.

To test this theory, it is interesting to study protein turnover, which regulates the balance between protein synthesis and degradation, because it could be particularly affected by aging and could lead to changes prelude to neuropathology. The turnover of proteins begins with their destruction, the catabolism of proteins is a key function of the digestive process. The amino acids resulting from these proteins thus degraded can be transformed into fuel for the Krebs cycle/citric acid (TCA).

Researchers led by Anja Schneider of the German Center for Neurodegenerative Diseases in Bonn and Eugenio Fornasiero of the University Medical Center Göttingen, both in Germany, measured the half-lives of more than 3,500 proteins in mouse brain. They found an average increase of 20 percent with age. **enter image description here**

For Alzheimer's disease, these life-extending proteins included:

  • the group of Tau proteins (MAPT)
  • ADAM10 which is correlated with the appearance of different types of synaptopathies, ranging from neurodevelopmental disorders, i.e. autism spectrum disorders, to neurodegenerative diseases, i.e. Alzheimer's disease.
  • DBN1 A decrease in the amount of this protein in the brain has been implicated as a possible contributing factor in the pathogenesis of memory impairment in Alzheimer's disease.
  • CTSDs which are implicated in the pathogenesis of several diseases, including breast cancer and possibly Alzheimer's disease.

For Parkinson's disease, they included:

  • Alpha-synuclein, a protein which in humans is encoded by the SNCA gene. Alpha-synuclein is a neuronal protein that regulates synaptic vesicle trafficking and the subsequent release of neurotransmitters. It is abundant in the brain, while smaller amounts are found in the heart, muscle, and other tissues. In the brain, alpha-synuclein is found primarily in the axon terminals of presynaptic neurons.

    Alpha-synuclein aggregates to form insoluble fibrils in pathological conditions characterized by Lewy bodies, such as Parkinson's disease, dementia with Lewy bodies, and multiple system atrophy. These disorders are known as synucleinopathies.

  • PARK7, Under oxidative conditions, the deglycase protein DJ-1 inhibits the aggregation of α-synuclein via its chaperone activity, thus functioning as a redox-sensitive chaperone and as an oxidative stress sensor. The functional protein DJ-1 has been shown to bind to metals and protect against metal-induced cytotoxicity of copper and mercury. Defects in this gene cause early-onset autosomal recessive Parkinson's disease

For ALS, they included:

  • TUBA4A, The alpha-4A chain of tubulin is a protein which in humans is encoded by the TUBA4A gene. This gene has only rarely been associated with ALS. Overall, ALS-related genes can be categorized into four groups based on the cellular pathways in which they are involved: (1) protein homeostasis; (2) homeostasis and RNA trafficking; (3) cytoskeletal dynamics; and (4) mitochondrial function.

    The reason TUBA4A might be associated with ALS is that motor neurons and skeletal muscle cells are known to be the largest cells in the human body. The significant length of these cells makes them highly dependent on the correct architecture of the cytoskeleton, the integrity of which is essential for the axonal transport necessary to maintain the integrity of synapses. Several mutations in the tubulin beta-4A (TUBA4A) gene destabilize microtubules by impairing repolymerization, likely contributing to axonal degeneration in MN.

  • SOD1, whose protective role against oxidative stress has been well studied, but whose mutations were previously only associated with 25% cases of familial ALS.

Conclusion The authors of this article observed a previously unknown alteration in proteostasis that is correlated with parsimonious protein turnover with high biosynthetic costs, revealing a global metabolic adaptation that preludes neurodegeneration.

However, nothing in this study explains how malformed, poorly localized proteins might appear. This study only shows a correlation between the half-life of proteins and certain neurodegenerative diseases.

Their results suggest that future therapeutic paradigms, aimed at addressing these metabolic adaptations, may be able to delay the onset of neurodegenerative disorders.

Among these we could mention certain factors related to metabolism which determine the half-life of proteins such as pH and temperature. It is well known that aging cells have an increasing pH: They become basic. when the daughter cells come from an aging mother cell, the daughter's age is "reset". A parent cell becomes less acidic as the parent cell ages. Daughter cells, on the other hand, have very acidic vacuoles.

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