Topics that don't need a category, or don't fit into any other existing category.

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

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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.


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...

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