Lecanemab slowed the rate of Alzheimer by 27% or 2.5%?

- Posted in Lecanemab slowed the rate of Alzheimer by 27% or 2.5%? by Uncategorized by

Biogen and Eisai said Lecanemab slowed the rate of cognitive decline by 27% in a large (1,795 participants), phase 3 clinical trial (CLARITY-AD) after two decades of consistent failure and murkier outcomes from similar, experimental drugs.

To say that Biogen and Eisai are happy is an understatement. This is also good news for other companies and scientists who based their career on the amyloid hypothesis.

21% of patients experienced brain swelling visible on PET scans.

The primary endpoint was measured with CDR-SB scale. The companies told of an improvement of 27%, with a score change of -0.45.

CDR-SB, which measures six cognitive domains including memory, problem solving, and personal care, produces scores ranging from 0 to 18. So -0.45 represents an improvement of 2.5% not 27%. According to some commentators, the -0.45 CDR-SB difference from placebo is small and should not be considered clinically significant, a more significant threshold would be closer to -0.9.

It's not clear to me where the 27% improvement comes from and we will have to wait for more information from the companies which will be presented at CTAD conference in San Francisco on November 29 - December 2, 2022.

https://www.statnews.com/2022/09/27/alzheimers-treatment-slowed-cognitive-decline-in-closely-watched-clinical-trial/?utm_campaign=rss

Does Resting Motor Threshold correlate with severity of Alzheimer's disease?

- Posted in Does Resting Motor Threshold correlate with severity of Alzheimer's disease? by English by

Resting motor threshold is the minimum intensity that evoked a visible contralateral involuntary finger twitch.

Resting motor threshold asymmetry is the absolute difference between the left and right RMT measurements.

Conflicting results have emerged from studies examining the potential of resting motor threshold as a neurophysiological marker for Alzheimer's disease diagnosis and progression.

In this study, the authors estimated the strength of the association between Resting motor threshold measurements and severity of cognitive impairment in a relatively large sample of clinical trial participants with mild to moderate Alzheimer's disease.

Resting motor threshold for each participant was determined by applying single-pulse transcranial magnetic stimulation repeated at varying intensities over left and right sides of the primary motor cortex.

Cognitive impairment was measured with the Montreal Cognitive Assessment and the Alzheimer Disease Assessment Scale - Cognitive scores.

Although the left and right resting motor threshold was lower in CDR 2 than in CDR 1 participants, neither RMT nor RMT asymmetry correlated significantly with cognitive test scores.

In conclusion, authors' study in a large sample size does not support the idea that resting motor threshold is a sensitive marker of cognitive decline/severity in Alzheimer's disease.

Read the original article on Pubmed

Alcohol Intake and dementias

- Posted in Alcohol Intake and dementias by English by

enter image description here Alzheimer's disease (Alzheimer's disease) is progressive brain disease that affects cognition, memory and behavior.

TDP-43 limbic-predominantly age-related encephalopathy (LATE) is a recently defined common neurodegenerative disorder that mimics the clinical symptoms of Alzheimer's disease.

LATE is a very common condition, typically it affects one third of people older than 75 years of age. This is in contrast to Alzheimer's disease pathology, which tends to level off and perhaps decrease in prevalence among persons beyond age 85 years.

TDP-43 is the major disease protein found in frontotemporal dementia and in amyotrophic lateral sclerosis.

At present, the risk factors involved in LATE and those that differentiate it from Alzheimer's disease are largely unknown.

Managing cardiovascular risk factors, maintaining an active lifestyle, and eating a balanced diet are associated with a reduced risk of AD or a lower rate of cognitive decline. Alcohol consumption is widespread and socially encouraged and is rarely associated with neurodegenerative diseases.

However, alcoholism leads to brain atrophy, and long-term alcohol use can damage almost every organ and system in the body. enter image description here

Authors of a new article used an algorithmic approach to identify important factors that distinguish patients with LATE and/or Alzheimer's disease from controls with significantly imbalanced data.

They analyzed two ROSMAP and NACC datasets and found that lifetime alcohol consumption was one of the most important lifestyle and environmental factors associated with LATE and Alzheimer's disease, and that their associations varied. In particular, the authors identified a specific subpopulation consisting of APOE-e4 carriers.

The authors found that for this subpopulation, light to moderate alcohol consumption was a protective factor against Alzheimer's disease and LATE, but its protective function against Alzheimer's disease appeared to be stronger than LATE.

The codes for authors' algorithms will be (hopefully) available at https://github.com/xinxingwu-uk/PFV.

Does ApoB mediate motor neuron degeneration in sporadic amyotrophic lateral sclerosis?

- Posted in Does ApoB mediate motor neuron degeneration in sporadic amyotrophic lateral sclerosis? by English by

A new publication by Jamie K Wong, and colleagues including two well known ALS scientists argues apolipoprotein B-100 in sporadic amyotrophic lateral sclerosis CSF is the putative agent responsible for inducing motor disability, motor neuron degeneration and pathological translocation of TDP-43.

While there are publications with similar claims about every week, this one sounds impressive, the scientists here have really worked hard to make sure they haven't left any stone unturned.

For a layperson like me, at first glance, this publication makes sense as there is a special relation between ALS and lipid metabolism. Apolipoproteins are proteins that bind lipids (oil-soluble substances such as fats, cholesterol and fat soluble vitamins) to form lipoproteins. They transport lipids in blood, cerebrospinal fluid and lymph. There are multiple classes of apolipoproteins and several sub-classes

ApoD level increases in nervous system with a large number of neurologic disorders inclusive of Alzheimer's disease, schizophrenia, and stroke. ApoE has been implicated in dementia and Alzheimer's disease.

So why not ApoB and ALS? Moreover overproduction of apolipoprotein B can result in lipid-induced endoplasmic reticulum stress and insulin resistance in the liver. ER stress leads to mislocalized misfolded proteins in cytosol, and half of ALS patients exhibit insulin resistance. In addition patients with ALS have higher levels of LDL-C, ApoB, and ApoB/ApoAI ratio already 20 years before diagnosis.

Yet this is not a study on humans but on mice and motor neurons in-vitro, and as usual a lot could be said about mice animal models of ALS. So maybe their claim, that ApoB is the agent responsible for inducing sporadic ALS, needs more work.

In addition a recent publication claimed that ALS patients that have elevated levels of ApoB in blood are associated with a lower risk of death. ApoB is also correlated with LDL (the "bad" cholesterol). Another study claimed the contrary. Yet another study did not find any evidence of association between lipoprotein or apolipoprotein levels and clinical findings.

There is also a lack of associations of cholesterol-lowering drugs (which lowers ApoB), antihypertensive drugs, and antidiabetics with the risk of ALS.

So we must remain cautious again, anyway even if this finding about ApoB and ALS was true, a commercial drug would be available only in 10 or 20 years.

Vestibular contribution to pathway integration deficits in individuals at genetic risk for Alzheimer's disease

- Posted in Vestibular contribution to pathway integration deficits in individuals at genetic risk for Alzheimer's disease by English by

Studies in arthropods have revealed the existence of mental maps of their position that are very effective in achieving their objective. These maps make it possible to determine their position and the direction to follow. Scientists call these maps "path integration". enter image description here Three important discoveries showed how these mental maps were implemented in the mammalian brain. * The first, in the early 1970s, is that hippocampal neurons, called place cells, respond to the position of the animal. * The second, in the early 1990s, is that neurons in neighboring regions, called head direction cells, respond in the direction of the animal's head. This makes it possible to manipulate movement information and see how the location and lead direction cells react. * The third finding was that the organization of neurons in the dorsomedial entorhinal cortex, named grid cells, closely resemble a sheet of squared paper organized in a hexagonal fashion and suggests that place cells can use grid cells to calculate distances. enter image description here Deficits of path integration, ie of these mental maps, manifest themselves at the onset of Alzheimer's disease. Decades before the expected onset of the disease subtle changes in pathway integration are also present in adults at genetic risk for Alzheimer's disease.

Previous studies of path integration have focused on tasks based on visual cues. The vestibular system is a barosensitive sensory organ, located in the inner ear, which contributes to the sensation of movement and balance in most mammals. So the study of these "path integration" maps must absolutely involve the vestibular system. This is realized in a new study published on MedRxiv, by Gillian Coughlan, Michael Hornberger and their colleagues.

One hundred and fifty participants aged 50-75 were recruited to take part in a research study at the University of East Anglia, Norwich, UK.

Saliva kits were sent to participants home and returned to the university the same day the saliva sample was taken to determine APOE genotype status. Sensor data was collected on the iPad-based assessment tool. The final sample size of 53 included 32 ε3ε3 carriers and 21 cross-sectional ε3ε4 carriers, each of whom completed the background cognitive test and vestibular task on the same day, as well as 3 homozygous APOE-ε4ε4 carriers.

The participants were asked to raise their legs (i.e. without touching the ground) and were turned over by the manipulator. Three seconds after the end of the flip, participants had to point the iPad as precisely as possible in the direction of the starting point, while still wearing the headband and earplugs. The iPad recorded vestibular data: acceleration, rotation and direction.

The scientists' results show impaired vestibular function, a deficiency in people at genetic risk for Alzheimer's disease. Vestibular function differentiated ε3ε4 carriers from ε3ε3 carriers, regardless of demographic background. Machine learning algorithms achieved significant performance in classifying genetic groups based on vestibular function, while univariate statistics failed to identify vestibular differences between APOE groups.

Animal and human studies also suggest a strong anatomical and functional interdependence between the vestibular system and the navigational system. Dysregulation of the vestibular system is associated with deficits in pathway integration.

Vestibular signals that influence pathway integration in preclinical Alzheimer's disease can help identify pathological changes before disease onset and thus guide treatment.

Identifying vestibular contributions to the cognitive phenotype of preclinical Alzheimer's disease is important because vestibular dysfunction is often present with treatable hearing loss. Additionally, vestibular balance training improved spatial orientation in monkeys with severe vestibular damage, suggesting that human adults with vestibular dysfunction, might respond to vestibular implant and/or intensive vestibular training.

Moreover, as the vestibular system has extensive connections with brain regions vulnerable to Alzheimer's disease, including the hippocampus, cingulate cortex, and parietal lobe, vestibular stimulation may indeed improve cognitive performance related to integrity of these brain regions, including disorientation and memory loss due to Alzheimer's disease.

Augmenting neurogenesis rescues memory impairments in Alzheimer’s disease

- Posted in Augmenting neurogenesis rescues memory impairments in Alzheimer’s disease by English by

Humans and other mammals have two hippocampi, one in each side of the brain. The hippocampus is part of the limbic system, and plays important roles in the consolidation of information from short-term memory to long-term memory, and in spatial memory that enables navigation. enter image description here

In the human, adult neurogenesis has been shown to occur at low levels, and in only three regions of the brain: the lateral ventricles, the amygdala and the hippocampus.

Hippocampal neurogenesis is impaired in Alzheimer’s disease patients, yet, it is unknown whether new neurons play a causative role in memory deficits. Dans un nouvel article Rachana Mishra, Orly Lazarov and colleagues show that immature neurons were actively recruited into the engram following a hippocampus-dependent task. An engram is the association of neuronal physical areas to external stimulus.

To examine whether the augmentation of adult hippocampal neurogenesis rescues learning and memory deficits in FAD, they generated four mouse model of familial Alzheimer disease with inducible neurogenesis. Bax gene deletion is known to enhance the survival of neural progenitor cells and led to increased neurogenesis. Bax belongs to the BCL2 family members which act as anti- or pro-apoptotic regulators, as usual, involved in a wide variety of cellular activities.

Targeted augmentation of neurogenesis in familial Alzheimer’s disease mice restored the number of new neurons in the engram, the dendritic spine density, and the transcription signature of both immature and mature neurons, ultimately leading to the rescue of memory. enter image description here

Chemogenetic inactivation of immature neurons following enhanced neurogenesis in Alzheimer’s disease, reversed mouse performance, and diminished memory. Notably, Alzheimer’s disease-linked App, ApoE, and Adam were of the top differentially expressed genes in the engram.

Collectively, these observations suggest that defective neurogenesis contributes to memory failure in Alzheimer’s disease.

First is the direct evidence that immature neurons in the DG play a role in hippocampus-dependent memory engram in wild-type and FAD mice.

Second, impairments in hippocampal neurogenesis cause defective engram formation in FAD and underlie memory deficits.

Third, an increasing level of neurogenesis rescues memory by restoring the engram.

Fourth, immature neurons are required for proper memory formation in FAD.

Fifth, augmenting neurogenesis rescues deficits in spine density in both immature and mature engram neurons in the DG of FAD mice.

Sixth, augmenting neurogenesis modulates the profile of immature and mature engram neurons in the DG to resemble the transcription profile of engram cells in wild-type mice.

Seventh, AD-linked signals, particularly App, Apoe, and Adam, play a role in the engram and are modulated following augmentation of neurogenesis and rescue of memory.

Synucleinopathy in Amyotrophic Lateral Sclerosis?

- Posted in Synucleinopathy in Amyotrophic Lateral Sclerosis? by Uncategorized by

I have for long thought that subtle distinctions between neurodegenerative diseases were blurring the understanding instead of making thing clearer.

In particular we know that ALS and FTD have something in common (TDP-43 aggregates), that Parkinson, dementia with Lewy bodies and Multiple System Atrophy are related (Alpha-synuclein aggregates (αSyn)), even some case of Alzheimer are related to ALS and FTD (Limbic-predominant age-related TDP-43 encephalopathy).

Yet an article to be published soon pushes the boundaries by hinting that αSyn may also play a pathological role in ALS, with αSyn-positive Lewy bodies co-aggregating alongside known ALS pathogenic proteins, such as SOD1 and TDP-43.

Around 50 cases of ALS/Parkinson commorbidities have already been described such this one, yet suggesting there is something fundamental behind ALS and Parkinson have never been suggested.

Many neurogenerative diseases are accompanied by accumulation of protein aggregates such as extracellular amyloid-β (in Alzheimer’s disease), intraneuronal hyper-phosphorylated tau (in Alzheimer’s disease), or α-synuclein (in Parkinson’s disease).

TDP-43 pathologies are widely varied and affects different cell types and brain regions. TDP-43 was reported to co-localize with other protein species characteristic in other neurogenerative diseases, namely Huntington’s disease, Parkinson’s disease, dementia with Lewy bodies, and Alzheimer’s disease. One reason may be that TDP-43 has regions of low complexity such its C-terminal domain, which could easily bind to other proteins.

The authors found a growing body of evidence that suggests that αSyn may also play a pathological role in ALS, with αSyn-positive Lewy bodies co-aggregating alongside known ALS pathogenic proteins, such as SOD1 and TDP-43. They discuss the involvement of αSyn in ALS and motor neuron disease pathology, and the current theories and strategies for therapeutics in ALS treatment, as well as those targeting αSyn for synucleinopathies, with a core focus on small molecule RNA technologies.

This does not explain the colocation of those proteins. An article published a year ago might point to a little discussed suspect: Karyopherins.

Karyopherins are proteins involved in transporting molecules between the cytoplasm and the nucleus of a eukaryotic cell. Most proteins require karyopherins to traverse the nuclear pore.

Karyopherins can act as importins (i.e. helping proteins get into the nucleus) or exportins (i.e. helping proteins get out of the nucleus). Energy for transport is derived from the Ran gradient.

Upon stress, several karyopherins stop shuttling between the nucleus and the cytoplasm and are sequestered in stress granules, cytoplasmic aggregates of ribonucleoprotein complexes...

Synucleinopathy in Amyotrophic Lateral Sclerosis?

- Posted in Synucleinopathy in Amyotrophic Lateral Sclerosis? by English by

I have long thought that the subtle distinctions between neurodegenerative diseases blur the understanding instead of making things clearer.

In particular we know that ALS and FTD have something in common (TDP-43 aggregates), that Parkinson, dementia with Lewy bodies and Multiple System Atrophy are related (Alpha-synuclein aggregates (αSyn)), even some case of Alzheimer are related to ALS and FTD (Limbic-predominant age-related TDP-43 encephalopathy).

Yet an article to be published soon pushes the boundaries by hinting that αSyn may also play a pathological role in ALS, with αSyn-positive Lewy bodies co-aggregating alongside known ALS pathogenic proteins, such as SOD1 and TDP-43.

Around 50 cases of ALS/Parkinson commorbidities have already been described such this one, yet suggesting there is something fundamental behind ALS and Parkinson have never been suggested.

Many neurogenerative diseases are accompanied by accumulation of protein aggregates such as extracellular amyloid-β (in Alzheimer’s disease), intraneuronal hyper-phosphorylated tau (in Alzheimer’s disease), or α-synuclein (in Parkinson’s disease).

TDP-43 pathologies are widely varied and affects different cell types and brain regions. TDP-43 was reported to co-localize with other protein species characteristic in other neurogenerative diseases, namely Huntington’s disease, Parkinson’s disease, dementia with Lewy bodies, and Alzheimer’s disease. One reason may be that TDP-43 has regions of low complexity such its C-terminal domain, which could easily bind to other proteins.

The authors found a growing body of evidence that suggests that αSyn may also play a pathological role in ALS, with αSyn-positive Lewy bodies co-aggregating alongside known ALS pathogenic proteins, such as SOD1 and TDP-43. They discuss the involvement of αSyn in ALS and motor neuron disease pathology, and the current theories and strategies for therapeutics in ALS treatment, as well as those targeting αSyn for synucleinopathies, with a core focus on small molecule RNA technologies.

This does not explain the colocation of those proteins. An article published a year ago might point to a little discussed suspect: Karyopherins.

Karyopherins are proteins involved in transporting molecules between the cytoplasm and the nucleus of a eukaryotic cell. Most proteins require karyopherins to traverse the nuclear pore.

Karyopherins can act as importins (i.e. helping proteins get into the nucleus) or exportins (i.e. helping proteins get out of the nucleus). Energy for transport is derived from the Ran gradient.

Upon stress, several karyopherins stop shuttling between the nucleus and the cytoplasm and are sequestered in stress granules, cytoplasmic aggregates of ribonucleoprotein complexes...

Time-restricted feeding rescues circadian disruption- aggravated progression of Alzheimer's disease in diabetic mice.

- Posted in Time-restricted feeding rescues circadian disruption- aggravated progression of Alzheimer's disease in diabetic mice. by English by

Aging is by far the most prominent risk factor for Alzheimer's disease, and both aging and Alzheimer's disease are associated with apparent metabolic alterations. Perturbed cerebral glucose metabolism, an invariant pathophysiological feature of Alzheimer's disease, may be a critical contributor to the pathogenesis of this disease. For this reason, Alzheimer's disease has sometime times being called "Type 3 diabetes mellitus".

Circadian rhythms, type 2 diabetes mellitus and Alzheimer's disease are closely related and interacted with each other.
The authors of a new article on MedRxiv have previously showed circadian disruption aggravated progression of Alzheimer's disease in T2DM mice. Time-restricted feeding is shown to be a potential synchronizer. This study aims to determine whether time-restricted feeding has a protect effect against the circadian disruption-aggravated progression of Alzheimer's disease in type 2 diabetes mellitus.

Six-week-old male diabetic mice and wildtype mice were kept under normal 12:12 light/dark cycles or altered 6:18 light/dark cycles with or without time-restricted feeding period. After eight weeks, three behavioral tests (open field test, novel object recognition test, barnes maze test were performed and the circadian gene expression, body weight, lipid levels and Alzheimer's disease-associated tau phosphorylation were evaluated.
The scientists found altered light/dark cycles contributed to disruptive circadian rhythms in the hippocampus of db/db mice, while time-restricted feeding prevented this effect. time-restricted feeding also ameliorated circadian disruption-aggravated increased body weight and lipid accumulation in db/db mice.

Importantly, the db/db mice under circadian disruption showed impaired cognition accompanied by increased tau phosphorylation, whereas time-restricted feeding reversed these changes. The altered light/dark cycles only affected circadian rhythms but not other indicators like plasma/liver lipids, cognition and tau phosphorylation in the wt/wt mice.

Collectively, time-restricted feeding has a protective effect against altered light/dark cycles-aggravated Alzheimer's disease progression in diabetic mice.

Read the original article on Pubmed

The bs-YHEDA peptide protects the brains of senile mice and thus recovers intelligence by reducing iron and free radicals.

- Posted in The bs-YHEDA peptide protects the brains of senile mice and thus recovers intelligence by reducing iron and free radicals. by English by

Iron accumulates in the brain with age and catalyzes free radical damage to neurons, thus playing a pathogenic role in Alzheimer's disease. To decrease the incidence of Alzheimer's disease, the authors synthesized the iron-affinitive peptide 5YHEDA to scavenge the excess iron in the senile brain: YHEDAYHEDAYHEDAYHEDAYHEDA.

However, the blood-brain barrier (a layer of cells around blood vessels in central nervous system) blocks the entrance of macromolecules into the brain, thus decreasing the therapeutic effects. Several receptors present in the BBB, including transferrin, the insulin receptor, and the low-density lipoprotein receptor (LDLR), are known to allow the passage of cognate protein ligands into the brain

To facilitate the entrance of the 5YHEDA peptide, the authors linked the low-density lipoprotein receptor-binding segment of ApoB-100 to 5YHEDA. Apolipoprotein B-100 (ApoB-100) is a lipid carrier. When recognized and bound by LDLR at the BBB, the complex can be converted to an endosome, subsequently resulting in transcytosis to the abluminal side of the BBB.

There, the apolipoprotein can be released for uptake by neurons and/or astrocytes when the pH is reduced, and the receptor is recycled to the cell surface.

Lipid-interactive regions and LDLR-binding regions are scattered in ApoB-100. The primary LDLR-binding region is located between amino acids 3359 and 3367, which consists of nine amino residues with the sequence “QSDIVAHLL”. To facilitate transport of the therapeutic YHEDA peptide across the BBB, the authors added the aforementioned LDLR-binding segment in ApoB-100 to the C-terminal of the synthesized therapeutic 5-YHEDA oligomer.

bs-5-YHEDA: YHEDAYHEDAYHEDAYHEDAYHEDA QSDIVAHLL

Using this method, they intended to deliver 5-YHEDA into the brains of senescent (SN) mice via LDLR-mediated endocytosis.

The SN Kunming mice exhibiting AD symptoms were divided into untreated, 5-YHEDA–treated, and bs-5- YHEDA–treated groups. Two hundred microliters of 20 mM 5-YHEDA or bs-5-YHEDA solution was intracardially injected into each mouse in the latter two groups weekly. The 6-month-old mice and the aging mice that did not display SN symptoms were used as the controls. Six weeks later, all mice underwent a 4-day MWM test after 1 day of adaptation. The path that the mouse swam to return to the underwater platform and the time spent were recorded to evaluate the individual’s cognitive ability

The results of intravenous injections of bs-5YHEDA into senescent mice demonstrated that bs-YHEDA entered the brain, increased ferriportin levels, reduced iron and free radical levels, decreased the consequences of neuronal necrosis and ameliorated cognitive disfunction without kidney or liver damage. bs-5YHEDA is a safe iron and free radical remover that potentially alleviates aging and Alzheimer's disease.

The bs-5-YHEDA–treated SN mice took only 57 seconds on average and swam 220 cm to return to the hidden platform in the MWM, nearly 25 seconds faster and 90 cm less than the untreated mice and the 5-YHEDA–treated SN mice , which suggests that the synthesized bs-5-YHEDA peptide prevented the deterioration of cognition and memory in the mice.

Read the original article on Pubmed


Please, help us continue to provide valuable information: